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Abstract:

The invention relates to pyrimidine compounds of the Formula I: or a
pharmaceutically acceptable salt thereof, wherein the constituent
variables are as defined herein, compositions comprising the compounds,
and methods for making and using the compounds.
##STR00001##

Description:

FIELD OF THE INVENTION

[0001] The invention relates to pyrimidine compounds, compositions
comprising such a compound, methods of synthesizing such compounds, and
methods for treating mTOR-related diseases comprising the administration
of an effective amount of such a compound. The invention relates to
methods for treating PI3K-related diseases comprising the administration
of an effective amount of such a compound. The invention also relates to
methods for treating hSMG-1-related diseases comprising the
administration of an effective amount of such a compound.

BACKGROUND OF THE INVENTION

[0002] Phosphatidylinositol (hereinafter abbreviated as "PI") is one of
the phospholipids in cell membranes. In recent years it has become clear
that PI plays an important role also in intracellular signal
transduction. It is well recognized in the art that PI (4,5) bisphosphate
(PI(4,5)P2 or PIP2) is degraded into diacylglycerol and inositol (1,4,5)
triphosphate by phospholipase C to induce activation of protein kinase C
and intracellular calcium mobilization, respectively [M. J. Berridge et
al., Nature, 312, 315 (1984); Y. Nishizuka, Science, 225, 1365 (1984)].

[0003] In the late 1980s, phosphatidylinositol-3 kinase ("PI3K") was found
to be an enzyme that phosphorylates the 3-position of the inositol ring
of phosphatidylinositol [D. Whitman et al., Nature, 332, 664 (1988)].
When PI3K was discovered, it was originally considered to be a single
enzyme. Recently however, it was clarified that a plurality of PI3K
subtypes exists. Three major subtypes of PI3Ks have now been identified
on the basis of their in vitro substrate specificity, and these three are
designated class I (a & b), class II, and class III [B. Vanhaesebroeck,
Trend in Biol. Sci., 22, 267 (1997)].

[0004] The class Ia PI3K subtype has been most extensively investigated to
date. Within the class Ia subtype there are three isoforms (α,
β, & δ) that exist as hetero dimers of a catalytic 110-kDa
subunit and regulatory subunits of 50-85 kDa. The regulatory subunits
contain SH2 domains that bind to phosphorylated tyrosine residues within
growth factor receptors or adaptor molecules and thereby localize PI3K to
the inner cell membrane. At the inner cell membrane PI3K converts PIP2 to
PIP3 (phosphatidylinositol-3,4,5-trisphosphate) that serves to localize
the downstream effectors PDK1 and Akt to the inner cell membrane where
Akt activation occurs. Activated Akt mediates a diverse array of effects
including inhibition of apoptosis, cell cycle progression, response to
insulin signaling, and cell proliferation. Class Ia PI3K subtypes also
contain Ras binding domains (RBD) that allow association with activated
Ras providing another mechanism for PI3K membrane localization.
Activated, oncogenic forms of growth factor receptors, Ras, and even PI3K
kinase have been shown to aberrantly elevate signaling in the
PI3K/Akt/mTOR pathway resulting in cell transformation. As a central
component of the PI3K/Akt/mTOR signaling pathway PI3K (particularly the
class Ia a isoform) has become a major therapeutic target in cancer drug
discovery.

[0005] Substrates for class I PI3Ks are PI, PI(4)P and PI(4,5)P2, with
PI(4,5)P2 being the most favored. Class I PI3Ks are further divided into
two groups, class Ia and class Ib, because of their activation mechanism
and associated regulatory subunits. The class Ib PI3K is p110γ that
is activated by interaction with G protein-coupled receptors. Interaction
between p110γ and G protein-coupled receptors is mediated by
regulatory subunits of 110, 87, and 84 kDa.

[0006] PI and PI(4)P are the known substrates for class II PI3Ks;
PI(4,5)P2 is not a substrate for the enzymes of this class. Class II
PI3Ks include PI3K C2α, C2β and C2γ isoforms, which
contain C2 domains at the C terminus, implying that their activity is
regulated by calcium ions.

[0007] The substrate for class III PI3Ks is PI only. A mechanism for
activation of the class III PI3Ks has not been clarified. Because each
subtype has its own mechanism for regulating activity, it is likely that
activation mechanism(s) depend on stimuli specific to each respective
class of PI3K.

[0008] The compound PI103
(3-(4-(4-morpholinyl)pyrido[3',':4,5]furo[3,2-d]pyrimidin-2-yl)phenol)
inhibits PI3K.sub.α and PI3K.sub.γ as well as the mTOR
complexes with IC50 values of 2, 3, and 50-80 nM respectively. I.P.
dosing in mice of this compound in human tumor xenograft models of cancer
demonstrated activity against a number of human tumor models, including
the glioblastoma (PTEN null U87MG), prostate (PC3), breast (MDA-MB-468
and MDA-MB-435) colon carcinoma (HCT 116); and ovarian carcinoma (SKOV3
and IGROV-1); (Raynaud et al, Pharmacologic Characterization of a Potent
Inhibitor of Class I Phosphatidylinositide 3-Kinases, Cancer Res. 2007
67: 5840-5850).

[0013] According to Verheijen, J. C. and Zask, A., Phosphatidylinositol
3-kinase (PI3K) inhibitors as anticancer drugs, Drugs Fut. 2007, 32(6):
537-547, [0014] Although it seems clear that inhibition of the α
isoform is essential for the antitumor activity of PI3K inhibitors, it is
not clear whether a more selective inhibitor of a particular PI3K isoform
may lead to fewer unwanted biological effects. It has recently been
reported that non-PI3Kα class I isoforms (PI3Kβ, δ and
γ) have the ability to induce oncogenic transformation of cells,
suggesting that nonisoform-specific inhibitors may offer enhanced
therapeutic potential over specific inhibitors. [0015] Selectivity versus
other related kinases is also an important consideration for the
development of PI3K inhibitors. While selective inhibitors may be
preferred in order to avoid unwanted side effects, there have been
reports that inhibition of multiple targets in the PI3K/Akt pathway
(e.g., PI3Kα and mTOR [mammalian target of rapamycin]) may lead to
greater efficacy. It is possible that lipid kinase inhibitors may
parallel protein kinase inhibitors in that nonselective inhibitors may
also be brought forward to the clinic.

[0016] Mammalian Target of Rapamycin, mTOR, is a cell-signaling protein
that regulates the response of tumor cells to nutrients and growth
factors, as well as controlling tumor blood supply through effects on
Vascular Endothelial Growth Factor, VEGF. Inhibitors of mTOR starve
cancer cells and shrink tumors by inhibiting the effect of mTOR. All mTOR
inhibitors bind to the mTOR kinase. This has at least two important
effects. First, mTOR is a downstream mediator of the PI3K/Akt pathway.
The PI3K/Akt pathway is thought to be over-activated in numerous cancers
and may account for the widespread response from various cancers to mTOR
inhibitors. The over-activation of the upstream pathway would normally
cause mTOR kinase to be over-activated as well. However, in the presence
of mTOR inhibitors, this process is blocked. The blocking effect prevents
mTOR from signaling to downstream pathways that control cell growth.
Over-activation of the PI3K/Akt kinase pathway is frequently associated
with mutations in the PTEN gene, which is common in many cancers and may
help predict what tumors will respond to mTOR inhibitors. The second
major effect of mTOR inhibition is anti-angiogenesis, via the lowering of
VEGF levels.

[0017] In lab tests, certain chemotherapy agents were found to be more
effective in the presence of mTOR inhibitors. George, J. N., et al.,
Cancer Research, 61, 1527-1532, 2001. Additional lab results have shown
that some rhabdomyosarcoma cells die in the presence of mTOR inhibitors.
The complete functions of the mTOR kinase and the effects of mTOR
inhibition are not completely understood.

[0018] There are three mTOR inhibitors, which have progressed into
clinical trials. These compounds are Wyeth's Torisel, also known as
42-(3-hydroxy-2-(hydroxymethyl)-rapamycin 2-methylpropanoate, CCI-779 or
Temsirolimus; Novartis' Everolimus, also known as
42-O-(2-hydroxyethyl)-rapamycin, or RAD 001; and Ariad's AP23573 also
known as 42-(dimethylphopsinoyl)-rapamycin. The FDA has approved Torisel
for the treatment of advanced renal cell carcinoma. In addition, Torisel
is active in a NOS/SCID xenograft mouse model of acute lymphoblastic
leukemia [Teachey et al, Blood, 107(3), 1149-1155, 2006]. On Mar. 30,
2009, the U.S. Food and Drug Administration (FDA) approved Everolimus
(AFINITOR®) for the treatment of patients with advanced renal cell
carcinoma. AP23573 has been given orphan drug and fast-track status by
the FDA for treatment of soft-tissue and bone sarcomas.

[0019] The three mTOR inhibitors have non-linear, although reproducible
pharmacokinetic profiles. Mean area under the curve (AUC) values for
these drugs increase at a less than dose related way. The three compounds
are all semi-synthetic derivatives of the natural macrolide antibiotic
rapamycin. It would be desirable to find fully synthetic compounds, which
inhibit mTOR that are more potent and exhibit improved pharmacokinetic
behaviors.

[0020] The most recently described PI3K family member was identified in
human cells and named human SMG-1 or hSMG-1. Yamashita (Genes Dev. 2001
15: 2215-2228) characterized two isoforms of hSMG-1 proteins, p430 and
p400, which are expressed in various cell lines of human, monkey, rat,
and mouse. Yamashita's p400 hSMG-1 isoform is a 3529-amino-acid protein
of 396,040 Daltons. Brumbaugh (Molecular Cell, Volume 14, Issue 5, 4 Jun.
2004, Pages 585-598) isolated a 3521 amino acid polypeptide with a
deduced molecular mass of 395 kDa. Brumbaugh's hSMG-1 is eight amino
acids shorter at the amino terminus than the protein isolated by
Yamashita.

[0021] Both hUpf1 and p53 are physiological targets for hSMG-1 in intact
cells. Rapamycin in the presence of purified recombinant FKBP12 does not
inhibit the kinase activity of hSMG-1. Wortmannin, the modified steroidal
anti-infective agent, and the purine caffeine inhibit the kinase activity
of hSMG-1 with IC50 values of ˜60 nM and 0.3 mM, respectively.
However, these are non-specific protein kinase inhibitors.

[0022] Specific inhibition of hSMG-1 is a potential therapeutic strategy
because inhibitors of hSMG-1 cause the accumulation of truncated p53
proteins from a premature translation termination codon (PTC) allele, as
well as the increase in the level of mRNA with PTC, opening the
possibility of the above strategy by specifically suppressing
nonsense-mediated mRNA decay (NMD) through the inhibition of hSMG-1.

[0023] One-fourth of all mutations in human genetic diseases and cancers
are of the type that can target the corresponding mRNA for NMD. Although
NMD protects cells against deleterious gain-of-function mutations caused
by the dominant negative effects of aberrant truncated proteins, there
are some cases in which the truncated protein does not show such an
effect, rather, it retains residual activity and can compensate for the
normal gene function. Thus, the specific inhibition of NMD may provide a
novel therapeutic strategy based on the type of mutation rather than on
the gene in which the mutation resides.

[0024] The inhibitors of SMG-1 can rescue the synthesis of mature proteins
through two independent mechanisms (i.e., the inhibition of NMD to
increase the mRNA level and the suppression of translational termination
that leads to the synthesis of a read-through mature protein product). In
this sense, the specific inhibitors of hSMG-1 will be of potential
therapeutic importance for all the genetic diseases associated with PTC
mutations.

[0025] As explained above, PI3K inhibitors, mTOR inhibitors, and hSMG-1
inhibitors are expected to be novel types of medicaments useful against
cell proliferation disorders, especially as carcinostatic agents. Thus,
it would be advantageous to have new PI3K inhibitors, mTOR inhibitors,
and hSMG-1 inhibitors as potential treatment regimens for mTOR-, PI3K-,
and hSMG-1-related diseases. The instant invention is directed to these
and other important ends.

SUMMARY OF THE INVENTION

[0026] In one aspect, the invention provides compounds of the Formula I:

##STR00002##

or a pharmaceutically acceptable salt thereof, wherein the constituent
variables are as defined below. In other aspects, the invention provides
compositions comprising a compound of the invention, and methods for
making compounds of the invention. In further aspects, the invention
provides methods for inhibiting PI3K, mTOR and hSMG-1 in a subject, and
methods for treating PI3K-related, mTOR-related and hSMG-1-related
disorders in a mammal in need thereof.

DETAILED DESCRIPTION OF THE INVENTION

[0027] In one aspect, the invention provides compounds of the Formula:

##STR00003##

or a pharmaceutically acceptable salt thereof wherein; R1 is
independently C1-C6alkyl-, C6-C14aryl-,
C1-C9heteroaryl-, halogen, or hydroxyl; p is 0, 1, 2, 3, or 4;
het is a bridged C5-C9heterobicyclyl- group containing at least
one oxygen atom, at least one nitrogen atom, and optionally additional
heteroatoms selected from oxygen, sulfur and nitrogen, and is connected
to the pyrimidinyl group through one of the nitrogen atoms; one of A is
C--R5 and the other two are N; Ar is C6-C14aryl- or
C1-C9heteroaryl- wherein the C6-C14aryl- or
C1-C9heteroaryl- is optionally substituted with from 1 to 4
substituents independently selected from C1-C6alkyl-, halogen,
haloalkyl-, hydroxyl, hydroxyl(C1-C6alkyl)-, H2N--,
aminoalkyl-, di(C1-C6alkyl)amino-, HO2C--,
(C1-C6alkoxy)carbonyl-, (C1-C6alkyl)carboxyl-,
di(C1-C6alkyl)amido-, H2NC(O)--,
(C1-C6alkyl)amido-, and O2N--; and wherein the
C6-C14aryl- or C1-C9heteroaryl- is bonded to the
pyrimidine core through a carbon atom of the C6-C14aryl- or
C1-C9heteroaryl-; R2 is H or C1-C6alkyl-;

[0296] In one aspect, the invention provides compounds of the Formula II:

##STR00004##

or a pharmaceutically acceptable salt thereof, wherein the constituent
variables are as defined for Formula I.

[0297] In one aspect, the invention provides compounds of the Formula III:

##STR00005##

or a pharmaceutically acceptable salt thereof, wherein the constituent
variables are as defined above for Formula I.

[0298] In one aspect, the invention provides compounds of the Formula IV:

##STR00006##

or a pharmaceutically acceptable salt thereof, wherein the constituent
variables are as defined above for Formula I.

[0299] In one aspect, the invention provides compounds of the Formula V:

##STR00007##

or a pharmaceutically acceptable salt thereof, wherein the constituent
variables are as defined above for Formula I.

[0300] In one aspect, the invention provides compounds of the Formula VI:

##STR00008##

or a pharmaceutically acceptable salt thereof, wherein the constituent
variables are as defined above for Formula I.

[0301] In one embodiment, p is 0.

[0302] In one embodiment, Ar is phenyl.

[0303] In one embodiment, R2 is H.

[0304] In one embodiment, R3 is R7R8N--.

[0305] In one embodiment, R7 is selected from
C1-C9heteroaryl- optionally substituted with from 1 to 3
substituents independently selected from C1-C9heterocyclyl-
optionally substituted by C1-C6alkyl-,
heterocyclyl(C1-C6alkyl)- optionally substituted by
C1-C6alkyl-, R10R11NC(O)--, and R10O--; and
C6-C14aryl- optionally substituted with from 1 to 3
substituents independently selected from C1-C9heterocyclyl-
optionally substituted by C1-C6alkyl-,
heterocyclyl(C1-C6alkyl)- optionally substituted by
C1-C6alkyl-, R10R11NC(O)--, and R10O--.

[0306] In one embodiment, R7 is C1-C9heteroaryl-.

[0307] In one embodiment, R7 is pyridyl-.

[0308] In one embodiment, R7 is 4-pyridyl-.

[0309] In one embodiment, R7 is C6-C14aryl- substituted
with C1-C9heterocyclyl- optionally substituted by
C1-C6alkyl-.

[0310] In one embodiment, R7 is C6-C14aryl- substituted
with heterocyclyl(C1-C6alkyl)- optionally substituted by
C1-C6alkyl-.

[0311] In one embodiment, R7 is C6-C14aryl- substituted
with R10R11NC(O)--.

[0463] In other aspects, the invention provides pharmaceutical
compositions comprising compounds or pharmaceutically acceptable salts of
the compounds of the present Formula I and a pharmaceutically acceptable
carrier.

[0464] In other aspects, the invention provides that the pharmaceutically
acceptable carrier suitable for oral administration and the composition
comprises an oral dosage form.

[0467] In other aspects, the invention provides a method of treating a
PI3K-related disorder, comprising administering to a mammal in need
thereof a compound of Formula I in an amount effective to treat a
PI3K-related disorder.

[0471] In other aspects, the invention provides a method of treating an
mTOR-related disorder, comprising administering to a mammal in need
thereof a compound of Formula I in an amount effective to treat an
mTOR-related disorder.

[0475] In other aspects, the invention provides a method of treating an
hSMG-1-related disorder, comprising administering to a mammal in need
thereof a compound of Formula I in an amount effective to treat an
hSMG-1-related disorder.

[0479] In other aspects, the invention provides a method of treating
advanced renal cell carcinoma, comprising administering to a mammal in
need thereof a compound of Formula I in an amount effective to treat
advanced renal cell carcinoma.

[0480] In other aspects, the invention provides a method of treating acute
lymphoblastic leukemia, comprising administering to a mammal in need
thereof a compound of Formula I in an amount effective to treat acute
lymphoblastic leukemia.

[0481] In other aspects, the invention provides a method of treating acute
malignant melanoma, comprising administering to a mammal in need thereof
a compound of Formula I in an amount effective to treat malignant
melanoma.

[0482] In other aspects, the invention provides a method of treating
soft-tissue or bone sarcoma, comprising administering to a mammal in need
thereof a compound of Formula I in an amount effective to treat
soft-tissue or bone sarcoma.

[0484] In other aspects, the invention provides a method of inhibiting
mTOR in a subject, comprising administering to a subject in need thereof
a compound of Formula I in an amount effective to inhibit mTOR.

[0485] In other aspects, the invention provides a method of inhibiting
PI3K in a subject, comprising administering to a subject in need thereof
a compound of Formula I in an amount effective to inhibit PI3K.

[0486] In other aspects, the invention provides a method of inhibiting
hSMG-1 in a subject, comprising administering to a subject in need
thereof a compound of Formula I in an amount effective to inhibit hSMG-1.

[0487] In other aspects, the invention provides a method of inhibiting
mTOR, PI3K, and hSMG-1 together in a subject, comprising administering to
a subject in need thereof a compound of Formula I in an amount effective
to inhibit mTOR, PI3K, and hSMG-1.

[0488] In other aspects, the invention provides a method of synthesizing a
compound of Formula 68:

##STR00009##

comprising reacting a pyrimidine compound of the formula 66:

##STR00010##

with a dioxaborolan-2-yl compound 67:

##STR00011##

to give 68 wherein the variables are as defined for Formula I.

[0489] In other aspects, the invention provides a method of synthesizing a
compound of Formula I further comprising, when N(R2)H is present,
reacting compound 68 with an acylating agent R3C(O)X, wherein X is a
leaving group, and wherein R3 is as defined in Formula I to give I:

[0491] Some compounds within the present invention possess one or more
chiral centers, and the present invention includes each separate
enantiomer of such compounds as well as mixtures of the enantiomers.
Where multiple chiral centers exist in compounds of the present
invention, the invention includes each combination as well as mixtures
thereof. All chiral, diastereomeric, and racemic forms of a structure are
intended, unless the specific stereochemistry or isomeric form is
specifically indicated. It is well known in the art how to prepare
optically active forms, such as by resolution of racemic forms or by
synthesis from optically active starting materials.

[0492] An "effective amount" when used in connection a compound of the
present invention of this invention is an amount effective for inhibiting
mTOR or PI3K in a subject.

DEFINITIONS

[0493] The following definitions are used in connection with the compounds
of the present invention unless the context indicates otherwise. In
general, the number of carbon atoms present in a given group is
designated "Cx-Cy", where x and y are the lower and upper
limits, respectively. For example, a group designated as
"C1-C6" contains from 1 to 6 carbon atoms. The carbon number as
used in the definitions herein refers to carbon backbone and carbon
branching, but does not include carbon atoms of the substituents, such as
alkoxy substitutions and the like.

[0494] "Acyl-" refers to a group having a straight, branched, or cyclic
configuration or a combination thereof, attached to the parent structure
through a carbonyl functionality. Such groups may be saturated or
unsaturated, aliphatic or aromatic, and carbocyclic or heterocyclic.
Examples of a C1-C8acyl- group include acetyl-, benzoyl-,
nicotinoyl-, propionyl-, isobutyryl-, oxalyl-, and the like. Lower-acyl
refers to acyl groups containing one to four carbons. An acyl group can
be unsubstituted or substituted with one or more of the following groups:
halogen, H2N--, (C1-C6alkyl)amino-,
di(C1-C6alkyl)amino-,
(C1-C6alkyl)C(O)N(C1-C3alkyl)-,
(C1-C6alkyl)carboxyamido-, HC(O)NH--, H2NC(O)--,
(C1-C6alkyl)NHC(O)--, di(C1-C6alkyl)NC(O)--, --CN,
hydroxyl, C1-C6alkoxy-, HO2C--,
(C1-C6alkoxy)carbonyl-, (C1-C6alkyl)C(O)--,
C6-C14aryl-, C1-C9heteroaryl-, or
C3-C8cycloalkyl-.

[0496] "Alkoxy-" refers to the group R--O-- where R is an alkyl group, as
defined below. Exemplary C1-C6alkoxy- groups include but are
not limited to methoxy, ethoxy, n-propoxy, 1-propoxy, n-butoxy and
t-butoxy. An alkoxy group can be unsubstituted or substituted with one or
more of the following groups: halogen, hydroxyl, C1-C6alkoxy-,
H2N--, (C1-C6alkyl)amino-, di(C1-C6alkyl)amino-,
(C1-C6alkyl)C(O)N(C1-C3alkyl)-,
(C1-C6alkyl)carboxyamido-, HC(O)NH--, H2NC(O)--,
(C1-C6alkyl)NHC(O)--, di(C1-C6alkyl)NC(O)--, NC--,
C1-C6alkoxy-, HO2C--, (C1-C6alkoxy)carbonyl-,
(C1-C6alkyl)C(O)--, C1-C9heteroaryl-,
C3-C8cycloalkyl-, C1-C6haloalkyl-,
amino(C1-C6alkyl)-, (C1-C6alkyl)carboxyl-,
C1-C6-carboxyamidoalkyl-, or O2N--.

[0497] "(Alkoxy)carbonyl-" refers to the group alkyl-O--C(O)--. Exemplary
(C1-C6alkoxy)carbonyl- groups include but are not limited to
methoxy, ethoxy, n-propoxy, 1-propoxy, n-butoxy and t-butoxy. An
(alkoxy)carbonyl group can be unsubstituted or substituted with one or
more of the following groups: halogen, hydroxyl, H2N--,
(C1-C6alkyl)amino-, di(C1-C6alkyl)amino-,
(C1-C6alkyl)C(O)N(C1-C3alkyl)-,
(C1-C6alkyl)carboxyamido-, HC(O)NH--, H2NC(O)--,
(C1-C6alkyl)NHC(O)--, di(C1-C6alkyl)NC(O)--, NC--,
C1-C6alkoxy-, HO2C--, (C1-C6alkoxy)carbonyl-,
(C1-C6alkyl)C(O)--, C1-C9heteroaryl-,
C3-C8cycloalkyl-, C1-C6haloalkyl-,
amino(C1-C6alkyl)-, (C1-C6alkyl)carboxyl-,
C1-C6-carboxyamidoalkyl-, or O2N--.

[0498] "Alkyl-" refers to a hydrocarbon chain that may be a straight chain
or branched chain, containing the indicated number of carbon atoms, for
example, a C1-C10alkyl- group may have from 1 to 10 (inclusive)
carbon atoms in it. In the absence of any numerical designation, "alkyl"
is a chain (straight or branched) having 1 to 6 (inclusive) carbon atoms
in it. Examples of C1-C6alkyl- groups include, but are not
limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl,
isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl. An
alkyl- group can be unsubstituted or substituted with one or more of the
following groups: halogen, H2N--, (C1-C6alkyl)amino-,
di(C1-C6alkyl)amino-,
(C1-C6alkyl)C(O)N(C1-C3alkyl)-,
(C1-C6alkyl)carboxyamido-, HC(O)NH--, H2NC(O)--,
(C1-C6alkyl)NHC(O)--, di(C1-C6alkyl)NC(O)--, NC--,
hydroxyl, C1-C6alkoxy-, C1-C6alkyl-, HO2C--,
(C1-C6alkoxy)carbonyl-, (C1-C6alkyl)C(O)--,
C6-C14aryl-, C1-C9heteroaryl-,
C3-C8cycloalkyl-, C1-C6haloalkyl-,
amino(C1-C6alkyl)-, (C1-C6alkyl)carboxyl-,
C1-C6-carboxyamidoalkyl-, or O2N--.

[0499] "(Alkyl)amido-" refers to a --C(O)NH-- group in which the nitrogen
atom of said group is attached to a C1-C6alkyl group, as
defined above. Representative examples of a (C1-C6alkyl)amido-
group include, but are not limited to, --C(O)NHCH3,
--C(O)NHCH2CH3, --C(O)NHCH2CH2CH3,
--C(O)NHCH2CH2CH2CH3,
--C(O)NHCH2CH2CH2CH2CH3,
--C(O)NHCH(CH3)2, --C(O)NHCH2CH(CH3)2,
--C(O)NHCH(CH3)CH2CH3, --C(O)NH--C(CH3)3 and
--C(O)NHCH2C(CH3)3.

[0500] "(Alkyl)amino-" refers to an --NH group, the nitrogen atom of said
group being attached to an alkyl group, as defined above. Representative
examples of an (C1-C6alkyl)amino- group include, but are not
limited to CH3NH--, CH3CH2NH--,
CH3CH2CH2NH--, CH3CH2CH2CH2NH--,
(CH3)2CHNH--, (CH3)2CHCH2NH--,
CH3CH2CH(CH3)NH-- and (CH3)3CNH--. An
(alkyl)amino group can be unsubstituted or substituted with one or more
of the following groups: halogen, H2N--,
(C1-C6alkyl)amino-, di(C1-C6alkyl)amino-,
(C1-C6alkyl)C(O)N(C1-C3alkyl)-,
(C1-C6alkyl)carboxyamido-, HC(O)NH--, H2NC(O)--,
(C1-C6alkyl)NHC(O)--, di(C1-C6alkyl)NC(O)--, NC--,
hydroxyl, C1-C6alkoxy-, HO2C--,
(C1-C6alkoxy)carbonyl-, (C1-C6alkyl)C(O)--,
C6-C14aryl-, C1-C9heteroaryl-,
C3-C8cycloalkyl-, C1-C6haloalkyl-,
amino(C1-C6alkyl)-, (C1-C6alkyl)carboxyl-,
C1-C6-carboxyamidoalkyl-, or O2N--.

[0501] "(Alkyl)carboxyamido-" refers to a --NHC(O)-- group in which the
carbonyl carbon atom of said group is attached to a C1-C6alkyl
group, as defined above. Representative examples of a
(C1-C6alkyl)carboxyamido- group include, but are not limited
to, --NHC(O)CH3, --NHC(O)CH2CH3,
--NHC(O)CH2CH2CH3,
--NHC(O)CH2CH2CH2CH3,
--NHC(O)CH2CH2CH2CH2CH3,
--NHC(O)CH(CH3)2, --NHC(O)CH2CH(CH3)2,
--NHC(O)CH(CH3)CH2CH3, --NHC(O)--C(CH3)3 and
--NHC(O)CH2C(CH3)3.

[0502] "Alkylcarboxyl-" refers to an alkyl group, defined above that is
attached to the parent structure through the oxygen atom of a carboxyl
(C(O)--O--) functionality. Examples of (C1-C6alkyl)carboxyl-
include acetoxy, propionoxy, propylcarboxyl, and isopentylcarboxyl.

[0503] "-Alkylene-", "-alkenylene-", and "-alkynylene-" refer to alkyl-,
alkenyl-, and alkynyl- groups, as defined above, having two points of
attachment within a chemical structure. Examples of
--C1-C6alkylene- include methylene (--CH2--), ethylene
(--CH2CH2--), propylene (--CH2CH2CH2--), and
dimethylpropylene (--CH2C(CH3)2CH2--). Likewise,
examples of --C2-C6alkenylene- include ethenylene
(--CH═CH-- and propenylene (--CH═CH--CH2--). Examples of
--C2-C6alkynylene- include ethynylene (--C≡C--) and
propynylene (--C≡C--CH2--).

[0505] "Amine-protecting group" refers to a radical when attached to a
nitrogen atom in a target molecule is capable of surviving subsequent
chemical reactions applied to the target molecule i.e. hydrogenation,
reaction with acylating agents, alkylation etc. The amine-protecting
group can later be removed. Amine protecting groups include, but are not
limited to, fluorenylmethoxycarbonyl (FMOC), tert-butoxycarbonyl (t-BOC),
benzyloxycarbonyl (Z), those of the acyl type (e.g., formyl, benzoyl,
trifluoroacetyl, p-tosyl, aryl- and alkylphosphoryl, phenyl- and
benzylsulfonyl, o-nitrophenylsulfenyl, o-nitrophenoxyacetyl), and of the
urethane type (e.g. tosyloxyalkyloxy-, cyclopentyloxy-, cyclohexyloxy-,
1,1-dimethylpropyloxy, 2-(p-biphenyl)-2-propyloxy- and
benzylthiocarbonyl). Amine-protecting groups are made using a reactive
agent capable of transferring an amine-protecting group to a nitrogen
atom in the target molecule. Examples of an amine-protecting agent
include, but are not limited to, C1-C6 aliphatic acid chlorides
or anhydrides, C6-C14arylcarboxylic acid chlorides or
anhydrides, t-butylchloroformate, di-tert-butyl dicarbonate,
butoxycarbonyloxyimino-2-phenylacetonitrile, t-butoxycarbonyl azide,
t-butylfluoroformate, fluorenylmethoxycarbonyl chloride,
fluorenylmethoxycarbonyl azide, fluorenylmethoxycarbonyl
benzotriazol-1-yl, (9-fluorenylmethoxycarbonyl)succinimidyl carbonate,
fluorenylmethoxycarbonyl pentafluorophexoxide, trichloroacetyl chloride,
methyl-, ethyl-, trichloromethyl- chloroformate, and other amine
protecting agents known in the art. Examples of such known
amine-protecting agents are found in pages 385-397 of T. W. Green, P. G.
M. Wuts, "Protective Groups in Organic Synthesis, Second Edition",
Wiley-Interscience, New York, 1991.

[0506] "Amino(alkyl)-" refers to an alkyl group, as defined above, wherein
one or more of the alkyl group's hydrogen atoms have been replaced with
--NH2. Representative examples of an amino(C1-C6alkyl)
group include, but are not limited to --CH2NH2,
--CH2CH2NH2, --CH2CH2CH2 NH2,
--CH2CH2CH2CH2NH2,
--CH2CH(NH2)CH3, --CH2CH(NH2)CH2CH3,
--CH(NH2)CH2CH3 and --C(CH3)2(CH2NH2),
--CH2CH2CH2CH2CH2NH2, and
--CH2CH2CH(NH2)CH2CH3. An amino(alkyl) group can
be unsubstituted or substituted with one or two of the following groups
C1-C6alkoxy, C6-C14aryl, C1-C9heteroaryl,
C3-C8cycloalkyl, and C1-C6alkyl.

[0507] "Aryl-" refers to an aromatic hydrocarbon group. Examples of an
C6-C14aryl- group include, but are not limited to, phenyl,
1-naphthyl, 2-naphthyl, 3-biphen-1-yl, anthryl, tetrahydronaphthyl,
fluorenyl, indanyl, biphenylenyl, and acenaphthenyl. An aryl group can be
unsubstituted or substituted with one or more of the following groups:
C1-C6alkyl-, halogen, haloalkyl-, hydroxyl,
hydroxyl(C1-C6alkyl)-, H2N--,
amino(C1-C6alkyl)-, di(C1-C6alkyl)amino-,
HO2C--, (C1-C6alkoxy)carbonyl-,
(C1-C6alkyl)carboxyl-, di(C1-C6alkyl)amido-,
H2NC(O)--, (C1-C6alkyl)amido-, or O2N--.

[0508] "(Aryl)alkyl-" refers to an alkyl group, as defined above, wherein
one or more of the alkyl group's hydrogen atoms have been replaced with
an aryl group as defined above. (C6-C14Aryl)alkyl- moieties
include benzyl, benzhydryl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl,
2-phenylpropyl, 1-naphthylmethyl, 2-naphthylmethyl and the like. An
(aryl)alkyl group can be unsubstituted or substituted with one or more of
the following groups: halogen, H2N--, hydroxyl,
(C1-C6alkyl)amino-, di(C1-C6alkyl)amino-,
(C1-C6alkyl)C(O)N(C1-C3alkyl)-,
(C1-C6alkyl)carboxyamido-, HC(O)NH--, H2NC(O)--,
(C1-C6alkyl)NHC(O)--, di(C1-C6alkyl)NC(O)--, NC--,
hydroxyl, C1-C6alkoxy-, C1-C6alkyl-, HO2C--,
(C1-C6alkoxy)carbonyl-, (C1-C6alkyl)C(O)--,
C6-C14aryl-, C1-C9heteroaryl-,
C3-C8cycloalkyl-, C1-C6haloalkyl-,
amino(C1-C6alkyl)-, (C1-C6alkyl)carboxyl-,
C1-C6-carboxyamidoalkyl-, or O2N--.

[0509] "Carboxyamidoalkyl-" refers to a primary carboxyamide (CONH2),
a secondary carboxyamide (CONHR') or a tertiary carboxyamide (CONR'R''),
where R' and R'' are the same or different substituent groups selected
from C1-C6alkyl-, C2-C6alkenyl,
C2-C6alkynyl, C6-C14aryl-,
C1-C9heteroaryl-, or C3-C8cycloalkyl-, attached to
the parent compound by an --C1-C6alkylene- group as defined
above. Exemplary C1-C6carboxyamidoalkyl- groups include but are
not limited to NH2C(O)--CH2--,
CH3NHC(O)--CH2CH2--,
(CH3)2NC(O)--CH2CH2CH2--,
CH2═CHCH2NHC(O)--CH2CH2CH2CH2--,
HCCCH2NHC(O)--CH2CH2CH2CH2CH2--,
C6H5NHC(O)--CH2CH2CH2CH2CH2CH2--,
3-pyridylNHC(O)--CH2CH(CH3)CH2CH2--, and
cyclopropyl-CH2NHC(O)--CH2CH2C(CH3)2CH2--.

[0510] "Cycloalkyl-" refers to a monocyclic, non-aromatic, saturated
hydrocarbon ring. Representative examples of a C3-C8cycloalkyl-
include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, and cyclooctyl. A cycloalkyl can be
unsubstituted or independently substituted with one or more of the
following groups: halogen, H2N--, (C1-C6alkyl)amino-,
di(C1-C6alkyl)amino-,
(C1-C6alkyl)C(O)N(C1-C3alkyl)-,
(C1-C6alkyl)carboxyamido-, HC(O)NH--, H2NC(O)--,
(C1-C6alkyl)NHC(O)--, di(C1-C6alkyl)NC(O)--, NC--,
hydroxyl, C1-C6alkoxy-, HO2C--,
(C1-C6alkoxy)carbonyl-, (C1-C6alkyl)C(O)--,
C6-C14aryl-, C1-C9heteroaryl-, or
C3-C8cycloalkyl-, C1-C6haloalkyl-,
amino(C1-C6alkyl)-, (C1-C6alkyl)carboxyl-,
C1-C6carboxyamidoalkyl-, or O2N--. Additionally, each of
any two hydrogen atoms on the same carbon atom of the carbocyclic ring
can be replaced by an oxygen atom to form an oxo (═O) substituent or
the two hydrogen atoms can be replaced by an alkylenedioxy group so that
the alkylenedioxy group, when taken together with the carbon atom to
which it is attached, form a 5- to 7-membered heterocycle containing two
oxygen atoms.

[0511] "Di(alkyl)amino-" refers to a nitrogen atom attached to two alkyl
groups, as defined above. Each alkyl group can be independently selected.
Representative examples of an di(C1-C6alkyl)amino- group
include, but are not limited to, --N(CH3)2,
--N(CH2CH3)(CH3), --N(CH2CH3)2,
--N(CH2CH2CH3)2,
--N(CH2CH2CH2CH3)2,
--N(CH(CH3)2)2, --N(CH(CH3)2)(CH3),
--N(CH2CH(CH3)2)2,
--NH(CH(CH3)CH2CH3)2, --N(C(CH3)3)2,
--N(C(CH3)3)(CH3), and --N(CH3)(CH2CH3).
The two alkyl groups on the nitrogen atom, when taken together with the
nitrogen to which they are attached, can form a 3- to 7-membered nitrogen
containing heterocycle wherein up to two of the carbon atoms of the
heterocycle can be replaced with --N(H)--,
--N(C3-C8cycloalkyl)-, --N(C6-C14aryl)-,
--N(C1-C9heteroaryl)-, --N(amino(C1-C6alkyl))-,
--N(C6-C14arylamino)-, --O--, --S--, --S(O)--, or
--S(O)2--.

[0513] "C1-C6Haloalkyl-" refers to a C1-C6alkyl group,
as defined above, wherein one or more of the C1-C6alkyl group's
hydrogen atoms has been replaced with --F, --Cl, --Br, or --I. Each
substitution can be independently selected from --F, --Cl, --Br, or --I.
Representative examples of an C1-C6haloalkyl- group include,
but are not limited to, --CHF, --CF3, CH2CF3,
--CH2CH2Br, --CH2CH2I, --CH2CH2CH2F,
--CH2CH2CH2Cl, --CH2CH2CH2CH2Br,
--CH2CH2CH2CH2I,
--CH2CH2CH2CH2CH2Br,
--CH2CH2CH2CH2CH2I, --CH2CH(Br)CH3,
--CH2CH(Cl)CH2CH3, --CH(F)CH2CH3 and
--C(CH3)2(CH2Cl).

[0514] "Heteroaryl-" refers to 5-10-membered mono and bicyclic aromatic
groups containing at least one heteroatom selected from oxygen, sulfur
and nitrogen. Examples of monocyclic C9heteroaryl- radicals include,
but are not limited to, oxazinyl, thiazinyl, diazinyl, triazinyl,
thiadiazoyl, tetrazinyl, imidazolyl, tetrazolyl, isoxazolyl, furanyl,
furazanyl, oxazolyl, thiazolyl, thiophenyl, pyrazolyl, triazolyl,
pyrimidinyl, N-pyridyl, 2-pyridyl, 3-pyridyl and 4-pyridyl. Examples of
bicyclic C1-C9heteroaryl- radicals include but are not limited
to, benzimidazolyl, indolyl, isoquinolinyl, benzofuranyl,
benzothiophenyl, indazolyl, quinolinyl, quinazolinyl, purinyl,
benzisoxazolyl, benzoxazolyl, benzthiazolyl, benzodiazolyl,
benzotriazolyl, isoindolyl, and indazolyl. The contemplated heteroaryl-
rings or ring systems have a minimum of 5 members. Therefore, for
example, C1heteroaryl- radicals would include but are not limited to
tetrazolyl, C2heteroaryl- radicals include but are not limited to
triazolyl, thiadiazoyl, and tetrazinyl, C9heteroaryl- radicals
include but are not limited to quinolinyl and isoquinolinyl. A heteroaryl
group can be unsubstituted or substituted with one or more of the
following groups: C1-C6alkyl-, halogen,
C1-C6haloalkyl-, hydroxyl, C1-C6hydroxylalkyl-,
H2N--, amino(C1-C6alkyl), di(C1-C6alkyl)amino-,
--COOH, (C1-C6alkoxy)carbonyl-,
(C1-C6alkyl)carboxyl-, di(C1-C6alkyl)amido-,
H2NC(O)--, (C1-C6alkyl)amido-, or O2N--.

[0515] "(Heteroaryl)alkyl-" refers to an alkyl group, as defined above,
wherein one or more of the alkyl group's hydrogen atoms have been
replaced with a heteroaryl- group as defined above. Examples of
(C1-C9heteroaryl)alkyl- moieties include 2-pyridylmethyl,
2-thiophenylethyl, 3-pyridylpropyl, 2-quinolinylmethyl, 2-indolylmethyl,
and the like. A (heteroaryl)alkyl group can be unsubstituted or
substituted with one or more of the following groups: halogen,
H2N--, hydroxyl, (C1-C6alkyl)amino-,
di(C1-C6alkyl)amino-,
(C1-C6alkyl)C(O)N(C1-C3alkyl)-,
(C1-C6alkyl)carboxyamido-, HC(O)NH--, H2NC(O)--,
(C1-C6alkyl)NHC(O)--, di(C1-C6alkyl)NC(O)--, NC--,
hydroxyl, C1-C6alkoxy-, HO2C--,
(C1-C6alkoxy)carbonyl-, (C1-C6alkyl)C(O)--,
C6-C14aryl-, C1-C9heteroaryl-,
C3-C6cycloalkyl-, C1-C6haloalkyl-,
amino(C1-C6alkyl)-, (C1-C6alkyl)carboxyl-,
C1-C6carboxyamidoalkyl-, or O2N--.

[0518] "Heterocyclyl(alkyl)-" refers to an alkyl group, as defined above,
wherein one or more of the alkyl group's hydrogen atoms have been
replaced with a heterocycle group as defined above.
Heterocyclyl(C1-C6alkyl)- moieties include 2-pyridylmethyl,
1-piperazinylethyl, 4-morpholinylpropyl, 6-piperazinylhexyl, and the
like. A heterocyclyl(alkyl) group can be unsubstituted or substituted
with one or more of the following groups: halogen, H2N--,
(C1-C6alkyl)amino-, di(C1-C6alkyl)amino-,
(C1-C6alkyl)C(O)N(C1-C3alkyl)-,
(C1-C6alkyl)carboxyamido-, HC(O)NH--, H2NC(O)--,
(C1-C6alkyl)NHC(O)--, di(C1-C6alkyl)NC(O)--, NC--,
hydroxyl, C1-C6alkoxy-, C1-C6alkyl-, HO2C--,
(C1-C6alkoxy)carbonyl-, (C1-C6alkyl)C(O)--, 4- to
7-membered monocyclic heterocycle, C6-C14aryl-,
C1-C9heteroaryl-, or C3-C8cycloalkyl-.

[0519] "Bridged heterobicyclyl- group containing at least one oxygen atom,
at least one nitrogen atom, and optionally additional heteroatoms
selected from oxygen, sulfur and nitrogen, and is connected to the
pyrimidinyl group through one of the nitrogen atoms;" refers to
5-10-membered bridged bicyclic groups containing at least one nitrogen
atom, one oxygen atom, and optionally additional heteroatom selected from
oxygen, sulfur and nitrogen. A bridged heterobicyclyl- group containing
at least one oxygen atom, at least one nitrogen atom, and optionally
additional heteroatoms selected from oxygen, sulfur and nitrogen, and is
connected to the pyrimidinyl group through one of the nitrogen atoms; may
be saturated or partially saturated. Exemplary bridged
C5-C9heterobicyclic rings containing at least one oxygen atom,
at least one nitrogen atom, and connected through one of the nitrogen
atom include but are not limited to 2-oxa-5-azabicyclo[2.2.1]heptane,
2-oxa-5-azabicyclo[2.2.2]octane, 7-oxa-2,5-diazabicyclo[2.2.2]octane,
2,7-dioxa-5-azabicyclo[2.2.2]octane, 5,7-dioxa-2-azabicyclo[2.2.2]octane,
3-oxa-6-azabicyclo[3.1.1]heptane, 6-oxa-3-azabicyclo[3.1.1]heptane,
6-oxa-3,8-diazabicyclo[3.2.1]octane, 3,6-dioxa-8-azabicyclo[3.2.1]octane,
3-oxa-8-azabicyclo[3.2.1]octane, 6,8-dioxa-3-azabicyclo[3.2.1]octane,
6,8-dioxa-3-azabicyclo[3.2.1]octane, 8-oxa-3-azabicyclo[3.2.1]octane,
3-oxa-7,9-diazabicyclo[3.3.1]nonane,
7-methyl-3-oxa-7,9-diazabicyclo[3.3.1]nonane,
9-oxa-3,7-diazabicyclo[3.3.1]none, 9-oxa-3-azabicyclo[3.3.1]nonane,
3-oxa-9-azabicyclo[3.3.1]nonane, and 3,7-dioxa-9-azabicyclo[3.3.1]nonane.
The contemplated heterocycle rings or ring systems have a minimum of 3
members. Therefore, for example, C5heterobicyclyl- radicals include
but are not limited to 2-oxa-5-azabicyclo[2.2.1]heptan-5-yl,
(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl,
(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl, and
6,8-dioxa-3-azabicyclo[3.2.1]octan-3-yl. C6heterobicyclyl- radicals
include but are not limited to 2-oxa-5-azabicyclo[2.2.2]octan-5-yl,
3-oxa-8-azabicyclo[3.2.1]octan-8-yl, 8-oxa-3-azabicyclo[3.2.1]octan-3-yl,
9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl,
7-methyl-3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-yl,
3-oxa-7,9-diazabicyclo[3.3.1]nonan-7-yl,
3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-yl, and
3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl. C7heterobicyclyl- radicals
include but are not limited to 9-oxa-3-azabicyclo[3.3.1]nonan-3-yl and
3-oxa-9-azabicyclo[3.3.1]nonan-9-yl.

[0520] "Hydroxylalkyl-" refers to an alkyl group, as defined above,
wherein one or more of the alkyl group's hydrogen atoms have been
replaced with hydroxyl groups. Examples of C1-C6hydroxylalkyl-
moieties include, for example, --CH2OH, --CH2CH2OH,
--CH2CH2CH2OH, --CH2CH(OH)CH2OH,
--CH2CH(OH)CH3, --CH(CH3)CH2OH and higher homologs.

[0521] "Leaving group" refers an atom or group (charged or uncharged) that
becomes detached from an atom in what is considered to be the residual or
main part of the substrate in a specified reaction. For example, in the
heterolytic solvolysis of benzyl bromide in acetic acid: the leaving
group is bromide. In the reaction of
N,N,N-trimethyl-1-phenylmethanaminium ion with methanethiolate, the
leaving group is trimethylamine. In the electrophilic nitration of
benzene, it is H.sup.+. The term has meaning only in relation to a
specified reaction. Examples of leaving groups include, for example,
carboxylates (i.e. CH3COO.sup.-, CF3CO2), F, water,
Cl.sup.-, Br.sup.-, I.sup.-, N3.sup.-, SCN.sup.-,
trichloroacetimidate, thiopyridyl, tertiary amines (i.e. trimethylamine),
phenoxides nitrophenoxide), and sulfonates (i.e. tosylate, mesylate,
triflate).

[0522] "Perfluoroalkyl-" refers to alkyl group, defined above, having two
or more fluorine atoms. Examples of a C1-C6perfluoroalkyl-
group include CF3, CH2CF3, CF2CF3 and
CH(CF3)2.

[0527] For therapeutic use, the pharmacologically active compounds of
Formula I will normally be administered as a pharmaceutical composition
comprising as the (or an) essential active ingredient at least one such
compound in association with a solid or liquid pharmaceutically
acceptable carrier and, optionally, with pharmaceutically acceptable
adjutants and excipients employing standard and conventional techniques.

[0528] The pharmaceutical compositions of this invention include suitable
dosage forms for oral, parenteral (including subcutaneous, intramuscular,
intradermal and intravenous) bronchial or nasal administration. Thus, if
a solid carrier is used, the preparation may be tableted, placed in a
hard gelatin capsule in powder or pellet form, or in the form of a troche
or lozenge. The solid carrier may contain conventional excipients such as
binding agents, fillers, tableting lubricants, disintegrants, wetting
agents and the like. The tablet may, if desired, be film coated by
conventional techniques. If a liquid carrier is employed, the preparation
may be in the form of a syrup, emulsion, soft gelatin capsule, sterile
vehicle for injection, an aqueous or non-aqueous liquid suspension, or
may be a dry product for reconstitution with water or other suitable
vehicle before use. Liquid preparations may contain conventional
additives such as suspending agents, emulsifying agents, wetting agents,
non-aqueous vehicle (including edible oils), preservatives, as well as
flavoring and/or coloring agents. For parenteral administration, a
vehicle normally will comprise sterile water, at least in large part,
although saline solutions, glucose solutions and like may be utilized.
Injectable suspensions also may be used, in which case conventional
suspending agents may be employed. Conventional preservatives, buffering
agents and the like also may be added to the parenteral dosage forms.
Particularly useful is the administration of a compound of Formula I
directly in parenteral formulations. The pharmaceutical compositions are
prepared by conventional techniques appropriate to the desired
preparation containing appropriate amounts of the active ingredient, that
is, the compound of Formula I according to the invention. See, for
example, Remington: The Science and Practice of Pharmacy, 20th Edition.
Baltimore, Md.: Lippincott Williams & Wilkins, 2000.

[0529] The dosage of the compounds of Formula I to achieve a therapeutic
effect will depend not only on such factors as the age, weight and sex of
the patient and mode of administration, but also on the degree of
potassium channel activating activity desired and the potency of the
particular compound being utilized for the particular disorder of disease
concerned. It is also contemplated that the treatment and dosage of the
particular compound may be administered in unit dosage form and that one
skilled in the art would adjust the unit dosage form accordingly to
reflect the relative level of activity. The decision as to the particular
dosage to be employed (and the number of times to be administered per day
is within the discretion of the physician, and may be varied by titration
of the dosage to the particular circumstances of this invention to
produce the desired therapeutic effect.

[0530] A suitable dose of a compound of Formula I or pharmaceutical
composition thereof for a mammal, including man, suffering from, or
likely to suffer from any condition as described herein is an amount of
active ingredient from about 0.01 mg/kg to 10 mg/kg body weight. For
parenteral administration, the dose may be in the range of 0.1 mg/kg to 1
mg/kg body weight for intravenous administration. For oral
administration, the dose may be in the range about 0.1 mg/kg to 5 mg/kg
body weight. The active ingredient will preferably be administered in
equal doses from one to four times a day. However, usually a small dosage
is administered, and the dosage is gradually increased until the optimal
dosage for the host under treatment is determined.

[0531] However, it will be understood that the amount of the compound
actually administered will be determined by a physician, in the light of
the relevant circumstances including the condition to be treated, the
choice of compound of be administered, the chosen route of
administration, the age, weight, and response of the individual patient,
and the severity of the patient's symptoms.

[0532] The amount of the compound of the present invention or a
pharmaceutically acceptable salt thereof that is effective for inhibiting
mTOR or PI3K in a subject. In addition, in vitro or in vivo assays can
optionally be employed to help identify optimal dosage ranges. The
precise dose to be employed can also depend on the route of
administration, the condition, the seriousness of the condition being
treated, as well as various physical factors related to the individual
being treated, and can be decided according to the judgment of a
health-care practitioner. Equivalent dosages may be administered over
various time periods including, but not limited to, about every 2 hours,
about every 6 hours, about every 8 hours, about every 12 hours, about
every 24 hours, about every 36 hours, about every 48 hours, about every
72 hours, about every week, about every two weeks, about every three
weeks, about every month, and about every two months. The number and
frequency of dosages corresponding to a completed course of therapy will
be determined according to the judgment of a health-care practitioner.
The effective dosage amounts described herein refer to total amounts
administered; that is, if more than one compound of the present invention
or a pharmaceutically acceptable salt thereof is administered, the
effective dosage amounts correspond to the total amount administered.

[0533] In one embodiment, the compound of the present invention or a
pharmaceutically acceptable salt thereof is administered concurrently
with another therapeutic agent.

[0534] In one embodiment, a composition comprising an effective amount of
a compound of the present invention or a pharmaceutically acceptable salt
thereof and an effective amount of another therapeutic agent within the
same composition can be administered.

[0535] Effective amounts of the other therapeutic agents are well known to
those skilled in the art. However, it is well within the skilled
artisan's purview to determine the other therapeutic agent's optimal
effective amount range. The compound of the present invention or a
pharmaceutically acceptable salt thereof and the other therapeutic agent
can act additively or, in one embodiment, synergistically. In one
embodiment, of the invention, where another therapeutic agent is
administered to an animal, the effective amount of the compound of the
present invention or a pharmaceutically acceptable salt thereof is less
than its effective amount would be where the other therapeutic agent is
not administered. In this case, without being bound by theory, it is
believed that the compound of the present invention or a pharmaceutically
acceptable salt thereof and the other therapeutic agent act
synergistically.

[0536] Procedures used to synthesize the compounds of the present
invention are described in Schemes 1-36 and are illustrated in the
examples. Reasonable variations of the described procedures are intended
to be within the scope of the present invention:

##STR00013##

Reaction of 2,4-dichloropyrimidine (1) with bridged
C5-C9heterobicycle compound 2 gave a mixture of regioisomers in
an 89:4 ratio, which were separated by silica gel chromatography as shown
in Scheme 1.

As shown in Scheme 3, reaction of 2,4,6-trichloropyrimidine (8) with
bridged C5-C9heterobicycle compound 2 gave a mixture of
regioisomers in an 83:11 ratio, which were separated by silica gel
chromatography.

##STR00016##

As shown in Scheme 4, reaction of
3-(2,6-dichloropyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (9) with
4-aminophenylboronic acid, pinacol ester gave the aniline intermediates
11 and 12 in a 16:15 ratio.

##STR00017##

As shown in Scheme 5, reaction of
3-(2,6-dichloropyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (9) with
4-nitrophenylboronic acid, pinacol ester gave the dicoupled material 15
as an insoluble material. The mono-coupled intermediates 13 and 14 were
obtained after silica gel chromatography in a 10:8 ratio.

##STR00018##

As shown in Scheme 6, reaction of
3-(2,6-dichloropyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (9) with
NaI/HI gave desired product (16) as the main peak along with a
dehalogenated impurity and starting material (9). None of the
2-chloro-6-iodopyrimidine isomer was detected.

##STR00019##

As shown in Scheme 7, reaction of
3-(6-chloro-2-(4-nitrophenyl)pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]oct-
ane (13) was uneventful.

##STR00020##

As shown in Scheme 7, reaction of
3-(6-chloro-2-(4-nitrophenyl)pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]oct-
ane (13) with 2-propanol also went smoothly. The nitro group was reduced
under the high temperature reaction conditions.

As shown in Scheme 10, the mono-coupled intermediate 14 described in
Scheme 5 also reacted with bridged C5-C9heterobicycle compound
2 to give isomeric intermediate 22 containing two bridged
C5-C9heterobicyclic rings.

##STR00023##

As shown in Scheme 11, reduction of the dicoupled material 15 described
in Scheme 5 followed by conversion to a urea or a carbamate gave the
4,4'-pyrimidine-2,4-diyl)diuriedo or dicarbamoyl intermediate 25.

##STR00024##

As shown in Scheme 12, reaction of
3-(2,6-dichloropyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (9) with
sodium hydroxide occurred selectively at position 2 of pyrimidine ring.

##STR00025##

As shown in Scheme 13, reaction of the 6-chloropyrimidine produced in the
previous scheme with bridged C5-C9heterobicycle compound 2 gave
a 2-hydroxypyridine intermediate (27), the hydroxyl group of which could
be reconverted to
3,3'-(2-chloropyrimidine-4,6-diyl)bis(8-oxa-3-azabicyclo[3.2.1]octane)
(28).

##STR00026##

As shown in Scheme 14, reaction of the 6-chloropyrimidine (26) produced
in Scheme 12 with a simple primary amine gave a 2-hydroxypyridine
intermediate (29), the hydroxyl group of which could be reconverted to
6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-2-chloro-N-isopropylpyrimidin-4-a-
mine (30).

##STR00027##

As shown in Scheme 15, reaction of the 6-chloropyrimidine (26) produced
in Scheme 12 with a simple secondary alcohol gave a 2-hydroxypyridine
intermediate (31), the hydroxyl group of which could be reconverted to
3-(2-chloro-6-isopropoxypyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane
(32).

##STR00028##

As shown in Scheme 16, reaction of 2,4,6-trichloropyrimidine (8) with
bridged C5-C9heterobicycle compound 33 gave regioisomer 34 as
the only isolated product. This is in contrast with the mixture of
regioisomers obtained in Scheme 3 using a less hindered bridged
C5-C9heterobicycle amine. Selective reaction at position 2 of
the pyrimidine ring with iodide gave the intermediate
8-(6-chloro-2-iodopyrimidin-4-yl)-3-oxa-8-azabicyclo[3.2.1]octane (35),
which served to differentiate the 2 and 6 positions of the pyrimidine
ring for subsequent Suzuki coupling.

##STR00029##

As shown in Scheme 17, reaction of 2,4,6-trichloropyrimidine (8) with
phenylboronic acid occurred at position 6 of the pyrimidine ring to give
2,4-dichloro-6-phenylpyrimidine (39) as the only isolated product. This
is in contrast to the amine displacement reactions of Schemes 3 and 16,
which occurred largely at the 4 position. Subsequent reaction with
bridged C5-C9heterobicycle compound 2 occurred as expected at
position 4.

##STR00030##

As shown in Scheme 18, reaction of
2,4-dichloro-6-(methylsulfonylmethyl)pyrimidine (42) with bridged
C5-C9heterobicycle compound 2 gave the monochloro compound 43
as the only isolated product.

##STR00031##

As shown in Scheme 19, the nitro group of
2,4,6-trichloro-5-nitropyrimidine (45) served to activate the 4 position
of the pyrimidine ring in preference to the 2 position. Reaction with the
bridged C5-C9heterobicycle compound 2 gave
3-(2,6-dichloro-5-nitropyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane
(46) as the only isolated product.

##STR00032##

In Scheme 20 is shown the synthesis of the
1-(pyridin-3-yl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl-
)urea (52) reagent for the Suzuki coupling reaction.

##STR00033##

As shown in Scheme 12,
4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloropyrimidin-2-ol (26)
produced in Scheme 12 was activated in the 2 position of the pyrimidine
ring towards Suzuki coupling by formation of the triflate (54).

##STR00034## ##STR00035##

An alternative synthesis of
8-(6-chloro-2-(4-nitrophenyl)pyrimidin-4-yl)-3-oxa-8-azabicyclo[3.2.1]oct-
ane (36) is shown in Scheme 22.

##STR00036##

As shown in Scheme 23, the trifluoromethyl group of
2,4-dichloro-6-(trifluoromethyl)pyrimidine (62) served to activate the 4
position of the pyrimidine ring in preference to the 2 position. Reaction
with the bridged C5-C9heterobicycle compound 2 gave
3-(2,6-dichloro-5-nitropyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane
(46) as the only isolated product.

##STR00037##

The preparation of the pyrimidine compounds I are shown in scheme 24.
Starting with bis activated pyrimidine 65 where X is a leaving group,
coupling with the appropriate bridged C5-C9heterobicycleyl
amine (R1)p-het-H reagent gave pyrimidine 66. Suzuki coupling
of 66 with the appropriate amino boronic acid pinacol ester 67, boronic
ester, or boronic acid leads to amino heterobicyclyl pyrimidine 68.
Transformation to the amido, ureido, or carbamoyl heterobicycle compounds
I is as described previously in scheme 2.

##STR00038##

An alternative synthesis of 2-(4-aminophenyl)pyrimidine (73) is shown in
Scheme 25.

##STR00039##

A synthesis of
8,8'-(2,5-dichloropyrimidine-4,6-diyl)bis(3-oxa-8-azabicyclo[3.2.1]octane-
) is shown in Scheme 26.

##STR00040##

A synthesis of
2-(4-aminophenyl)-6-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-N-isopropyl-
pyrimidin-4-amine) is shown in Scheme 27.

##STR00041##

A synthesis of
6-chloro-2-(4-nitrophenyl)-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-amine
from compound 59 is shown in Scheme 28.

##STR00042##

A synthesis of
6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-2-(4-nitrophenyl)-N-(tetrahydro-2-
H-pyran-4-yl)pyrimidin-4-amine from compound 36 is shown in Scheme 29.

##STR00043##

A synthesis of
2-(4-aminophenyl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-(2-(methylsul-
fonyl)ethyl)pyrimidin-4-amine from compound 59 is shown in Scheme 30.

##STR00044##

A synthesis of
2-(4-aminophenyl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N,N-diethylpyri-
midin-4-amine from compound 33 is shown in Scheme 31.

##STR00045##

A synthesis of
1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-2-chloropyrimidin-4-yl)-N,N-di-
methylmethanamine from compound 33 is shown in Scheme 32.

##STR00046##

A synthesis of the urea boronic esters from the isocyanate boronates is
shown in Scheme 33.

##STR00047##

A synthesis of the
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((dimethylamino)methyl)py-
rimidin-2-yl)phenyl)-3-ureas from the urea boronic esters is shown in
Scheme 34.

##STR00048##

A synthesis of the
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((dimethylamino)methyl)py-
rimidin-2-yl)phenyl)-3-ureas from
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline is shown in Scheme
35.

##STR00049##

[0537] Stille coupling on compound 36 as prepared in Scheme 16 followed by
hydrogenation gave 75. Transformation of the aniline in 75 into urea or
carbamate compounds was effected as before as shown in Scheme 36.

[0538] One of skill in the art will recognize that Schemes 1-36 can be
adapted to produce the other compounds of Formula I and pharmaceutically
acceptable salts of compounds of Formula I according to the present
invention.

EXAMPLES

[0539] The following abbreviations are used herein and have the indicated
definitions: ATP is adenosine triphosphate, βME is
2-mercaptoethanol, BOC is tertiary-butyloxycarbonyl, and BSA is Bovine
Serum Albumin. Celite® is flux-calcined diatomaceous earth. Celite®
is a registered trademark of World Minerals Inc. CHAPS is
(3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid, DELFIA is
Dissociation-Enhanced Lanthanide Fluorescent Immunoassay. DIPEA or
Hunig's Base is diisopropylethylamine, DME is 1,2-dimethoxyethane, DMF is
N,N-dimethylformamide, DMSO is dimethylsulfoxide, DPBS is Dulbecco's
Phosphate Buffered Saline Formulation. DTT is
(2S,3S)-1,4-bis-sulfanylbutane-2,3-diol or dithiothreitol, EDTA is
ethylenediaminetetraacetic acid, EGTA is ethylene glycol tetraacetic
acid, EtOAc is ethyl acetate, FLAG-TOR is a FLAG-tagged TOR protein,
HEPES is 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid, HPLC is
high-pressure liquid chromatography. LC/MS is Liquid Chromatography/Mass
Spectrometry, microcrystin LR is the cyclic heptapeptide hepatotoxin
produced Microcystis aeruginosa containing the amino acids leucine (L)
and arginine (R) in the variable positions, MS is mass spectrometry, mTOR
is Mammalian Target of Rapamycin (a protein), MTS is
3-(4,5-dimethylthiazol-2-yl)-5-(3
carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt, PBS
is phosphate-buffered saline (pH 7.4), PI3K is phosphoinositide 3-kinase
(an enzyme). Ni(Ra) is Raney® nickel, a sponge-metal catalyst produced
when a block of nickel-aluminum alloy is treated with concentrated sodium
hydroxide. Raney® is a registered trademark of W. R. Grace and
Company. RPMI 1640 is a buffer (Sigma-Aldrich Corp., St. Louis, Mo.,
USA), RT is retention time, SDS is dodecyl sulfate (sodium salt), SRB is
Sulforhodamine B, TAMRA is tetramethyl-6-carboxyrhodamine, TFA is
trifluoroacetic acid, THF is tetrahydrofuran, and TRIS is
tris(hydroxymethyl)aminomethane.

Synthetic Methods

[0540] The following methods outline the synthesis of the Examples of the
present invention.

Scheme 1

3-(2-Chloro-pyrimidin-4-yl)-8-oxa-3-aza-bicyclo[3.2.1]octane (3)

[0541] A 745 mg (5 mmol) portion 2,4-dichloropyrimidine (1) was dissolved
in 20 mL EtOH at 0 C. 8-oxa-3-aza-bicyclo[3.2.1]octane hydrochloride (2,
748 mg, 5 mmol) was added followed by the addition of NEt3 (2.1 mL,
15 mmol). The mixture was stirred for 1 hour at ambient temperature. The
mixture was concentrated, dissolved in EtOAc and washed with saturated
NaHCO3. The aqueous phase was extracted with EtOAc and the combined
organic phases were dried (MgSO4), filtered and concentrated. The
mixture was purified by silica gel chromatography (20-70% EtOAc in
hexanes) to give 1,003 mg (4.4 mmol, 89%) of
3-(2-chloro-pyrimidin-4-yl)-8-oxa-3-aza-bicyclo[3.2.1]octane (3) along
with 50 mg (0.22 mmol, 4%) of
3-(4-chloro-pyrimidin-2-yl)-8-oxa-3-aza-bicyclo[3.2.1]octane (4).

Scheme 2

General Conditions for Suzuki Coupling (Formation of 6)

[0542] Aryl chloride 5 (1 eq) and 4-aminophenylboronic acid, pinacol ester
(1.1 eq) are dissolved in toluene (10 mL/mmol) and EtOH (6 mL/mmol). A 2M
solution of Na2CO3 is added (2 mL/mmol, 4 eq) and the mixture
is degassed by leading a stream of nitrogen through the solution.
Tetrakis(triphenylphosphine) palladium is added (5-10 mol %) and the
mixture is heated under reflux until the reaction is complete (4-48
hours). The reaction mixture is diluted with EtOAc, washed with saturated
NaHCO3 and the organic phase is dried (MgSO4), filtered and
concentrated. The mixture is purified by silica gel chromatography using
a gradient of ethyl acetate in hexanes.

Illustrative Example for Suzuki Coupling

4-[4-(8-Oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl]aniline

[0543] 3-(2-Chloro-pyrimidin-4-yl)-8-oxa-3-aza-bicyclo[3.2.1]octane (3,
564 mg, 2.5 mmol) and 4-aminophenylboronic acid, pinacol ester (602 mg,
2.75 mmol) are dissolved in toluene (25 mL) and EtOH (15 mL). A 2M
solution of Na2CO3 is added (5 mL) and the mixture is degassed
by leading a stream of nitrogen through the solution.
Tetrakis(triphenylphosphine) palladium is added (144 mg, 5 mol %) and the
mixture is heated under reflux for 48 hours. The mixture is diluted with
EtOAc, washed with saturated NaHCO3, the organic phase is dried
(MgSO4), filtered, and concentrated. The mixture is purified by
silica gel chromatography using a gradient of ethyl acetate in hexanes
(40-100%) to give 576 mg (2.04 mmol, 82%) of
4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl]aniline. RT 1.51,
M+H=283.1

General Conditions for Urea or Carbamate Formation (Conversion of 6 into
7)

[0544] Aniline 6 (1 eq) is dissolved in dichloromethane (10 mL/mmol) and
NEt3 is added (0.65 mL per mmol of 6). This solution is added in
drops to a solution of triphosgene (0.5 eq) in dichloromethane (10 mL per
mmol of 6). The mixture is stirred for 5-30 min at room temperature and
is then added to excess (3-10 eq) alcohol or amine in dichloromethane or
THF. The mixture is stirred at room temperature (4-24 hours),
concentrated, and purified by HPLC.

Illustrative Example for Urea or Carbamate Formation (Conversion of 6 into
7)

[0545] A 0.36 mmol portion of
4-[4-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-pyrimidin-2-yl]-phenylamine
(101 mg) was dissolved in dichloromethane (3 mL) and NEt3 was added
(0.195 mL). This solution was added in drops to a solution of 53 mg (0.18
mmol) triphosgene in dichloromethane (3 mL). After 5 min, the solution
was divided over 3 vials containing excess amine or alcohol in
dichloromethane or THF. After stirring for 4 hours at room temperature
the solvents were evaporated and the mixtures were purified by HPLC
(Waters, TFA buffers) to give the following products:

[0551] 3-(2,6-Dichloropyrimidin-4-yl)-8-oxa-3-aza-bicyclo[3.2.1]octane (9)
was dissolved in toluene (24 mL) and EtOH (16 mL). To this solution was
added 4-nitrophenylboronic acid pinacol ester (1.25 g, 5 mmol) and 8 mL
of a 2M solution of Na2CO3. The mixture was degassed by
bubbling nitrogen through the solution. Pd(PPh3)4 (231 mg, 0.2
mmol) was added and the mixture was heated under reflux overnight. The
mixture was filtered. The solids, consisting of
3-[2,6-bis-(4-nitro-phenyl)-pyrimidin-4-yl]-8-oxa-3-aza-bicyclo[3.2.1]oct-
ane (15), were collected and washed with water and dichloromethane. The
combined filtrates were concentrated, dissolved in dichloromethane and
washed with saturated NaHCO3. The organic phase was dried
(MgSO4), filtered and concentrated. The crude product was added to a
silica gel column and was eluted with 10-50% ethyl acetate in hexanes.
Collected fractions were concentrated to give
3-[6-chloro-2-(4-nitro-phenyl)-pyrimidin-4-yl]-8-oxa-3-aza-bicyclo[3.2.1]-
octane (13, 135 mg, 10%) along with
3-[2-chloro-6-(4-nitro-phenyl)-pyrimidin-4-yl]-8-oxa-3-aza-bicyclo[3.2.1]-
octane (14, 110 mg, 8%).

[0552] In a 20 mL scintillation vial was placed
3-(2,6-dichloropyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (9, 780
mg, 3 mmol) in chloroform (2 ml) to give a very light yellow solution.
Sodium iodide (749 mg, 5 mmol) was added to give a suspension. The
mixture was cooled to 0° C. and an aqueous solution (57% w/w) of
hydrogen iodide (0.356 ml, 2.70 mmol) was added, resulting in a thick
yellow precipitate. The mixture was stirred at room temperature for 16
hours. LCMS indicated only a trace of product being formed. Additional
aqueous. HI (356 μL) was added and the mixture was stirred at room
temperature for 64 hours. Additional aqueous HI was added (712 μL) and
the suspension was stirred for an additional 7 hours. LCMS showed the
presence of the desired product as the main peak along with a
dehalogenated impurity and starting material. The mixture was diluted
with water and solid K2CO3 was added to pH˜8. The aqueous
phase was extracted with dichloromethane. The organic phase was washed
with aqueous sodium thiosulfate to decolorize, dried over MgSO4,
filtered and concentrated. The crude product was added to a silica gel
column and was eluted with ethyl acetate in hexanes (15-40%). Collected
fractions were concentrated to give 588 mg (1.7 mmol, 56%) of a white
solid, which was a mixture of the desired product containing
approximately 20% starting material. The mixture was carried on to the
next step.

[0553] In a 0.5-2 mL microwave vial was placed
3-(6-chloro-2-iodopyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (16, 50
mg, 0.142 mmol) and
4,4,5,5-tetramethyl-2-(4-nitrophenyl)-1,3,2-dioxaborolane (35.4 mg, 0.142
mmol) in DME (1.5 ml) to give an orange solution. Na2CO3 (2M
solution in water) (0.284 ml, 0.569 mmol) was added. The mixture was
degassed by bubbling nitrogen through the solution. Pd(PPh3)4
(16.43 mg, 0.014 mmol) was added and the mixture was heated under
microwave irradiation for 60 min at 100° C. The mixture was
diluted with ethyl acetate and washed with a saturated solution of
NaHCO3. The organic phase was dried (MgSO4) and concentrated.
The crude product was added to a silica gel column and was eluted with
ethyl acetate in hexanes (10-25%). Collected fractions were concentrated
to give 39 mg (0.11 mmol, 79%) of the title compound as an
off-white/yellow solid. The thus obtained compound was identical to the
same compound prepared according to Scheme 5.

[0554] In a 2-5 mL microwave vial was placed
3-(6-chloro-2-(4-nitrophenyl)pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]oct-
ane (13, 70 mg, 0.202 mmol) in iPrNH2 (4 ml) to give a yellow
suspension. The reaction was heated under microwave irradiation at
140° C. for 90 min. The mixture was concentrated, dissolved in
dichloromethane and washed with sat NaHCO3. The organic phase was
dried over MgSO4, filtered and concentrated to give 74 mg of the
title compound as a yellow solid (99%).

[0555] In a 250 mL round-bottomed flask was placed
6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-N-isopropyl-2-(4-nitrophenyl)pyri-
midin-4-amine (17, 74 mg, 0.200 mmol) in 2-propanol (7 mL) and
dichloromethane (7 mL) to give a yellow solution. A catalytic amount of
Pd on charcoal (wet) was added and the mixture was stirred under a
hydrogen atmosphere for 1 hour. The mixture was filtered over Celite®,
rinsed with dichloromethane and concentrated to give the title compound
in quantitative yield.

[0556] The following products were prepared from
[2-(4-amino-phenyl)-6-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-pyrimidin-4-yl-
]-isopropyl-amine (18), using the general procedure from scheme 2 for the
preparation of 7:

[0561] In a 2-5 mL microwave vial was placed
3-(6-chloro-2-(4-nitrophenyl)pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]oct-
ane (13, 70 mg, 0.202 mmol) in 2-propanol (4 mL) to give a yellow
suspension. Sodium hydride (60% in oil, 32.3 mg, 0.807 mmol) was added
and the mixture was stirred until no further formation of hydrogen gas
was observed. The reaction was heated under microwave irradiation at
140° C. for 30 min to give a bright orange suspension. Work-up:
the solvents were evaporated. The residue was dissolved in
dichloromethane and washed with sat NaHCO3. The organic phase was
dried over MgSO4, filtered and concentrated to give the title
compound in a quantitative yield.

[0562] The following products were prepared from
4-[4-isopropoxy-6-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-pyrimidin-2-yl]-ph-
enylamine (19), using the general procedure from scheme 2 for the
preparation of 7:

[0567] In a 100 mL round-bottomed flask was placed
3-(6-chloro-2-(4-nitrophenyl)pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]oct-
ane (13, 135 mg, 0.39 mmol) in dioxane (5 ml).
8-Oxa-3-azabicyclo[3.2.1]octane, HCl (2, 0.15 g, 1 mmol) and
triethylamine (0.28 ml, 2 mmol) were added. The mixture was stirred at
80° C. for 16 hours. DIPEA was added (0.3 mL) and stirring was
continued at 80° C. for 64 hours. The reaction mixture was diluted
with ethyl acetate and washed with sat NaHCO3 followed by 0.1 N HCl.
The organic phase was dried over MgSO4, filtered and concentrated.
The crude product was added to a silica gel column and eluted with ethyl
acetate in hexanes (10-50%) to give 65 mg of the title compound (0.15
mmol, 39%).

[0568] In a 250 mL round-bottomed flask was placed
3,3'-(2-(4-nitrophenyl)pyrimidine-4,6-diyl)bis(8-oxa-3-azabicyclo[3.2.1]o-
ctane) (20, 65 mg, 0.15 mmol) in ethanol (3 ml). A catalytic amount of Pd
on charcoal (wet) was added and the mixture was stirred under a hydrogen
atmosphere for 16 hours. The mixture was filtered over Celite®, rinsed
with dichloromethane and concentrated to give a quantitative yield of the
title compound along with an impurity (the N-ethyl aniline product). The
crude mixture was reacted in the next step.

[0569] The following products were prepared from
4-(4,6-di(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrimidin-2-yl)aniline (21)
using the general procedure from scheme 2 for the preparation of 7:

[0572] Using a solution of 4-(4-methylpiperazin-1-yl)aniline in
dichloromethane, the title compound was obtained in a yield of 16 mg,
43%. RT 1.74. M+H=611.3.

[0573] The following products were prepared from the N-ethyl impurity in
4-(4,6-di(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrimidin-2-yl)aniline (21)
using the general procedure from scheme 2 for the preparation of 7:

[0576] In a 100 mL round-bottomed flask was placed
3-[2-chloro-6-(4-nitro-phenyl)-pyrimidin-4-yl]-8-oxa-3-aza-bicyclo[3.2.1]-
octane (14, 110 mg, 0.32 mmol) in dioxane (5 ml).
8-Oxa-3-azabicyclo[3.2.1]octane, HCl (2, 0.15 g, 1 mmol) and
triethylamine (0.28 ml, 2 mmol) were added. The mixture was stirred at
80° C. for 16 hours. DIPEA was added (0.3 mL) and stirring was
continued at 80° C. for 64 hours. The reaction mixture was diluted
with ethyl acetate and washed with sat NaHCO3. The solids between
the organic phase and aqueous phase were dissolved in dichloromethane and
washed with saturated NaHCO3. The combined organic phases were dried
over MgSO4, filtered and concentrated. The crude product was added
to a silica gel column and eluted with ethyl acetate in hexanes (10-40%)
to give 89 mg of the title compound (0.21 mmol, 65%).

[0577] In a 250 mL round-bottomed flask was placed
3,3'-(6-(4-nitrophenyl)pyrimidine-2,4-diyl)bis(8-oxa-3-azabicyclo[3.2.1]o-
ctane) (22, 89 mg, 0.21 mmol) in ethanol (3 ml). A catalytic amount of Pd
on charcoal (wet) was added and the mixture was stirred under a hydrogen
atmosphere for 16 hours. The mixture was filtered over Celite®, rinsed
with dichloromethane and concentrated to give a quantitative yield of the
title compound along with an impurity (the N-ethyl aniline product). The
crude mixture was reacted in the next step.

[0578] The following products were prepared from
4-(2,6-di(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrimidin-4-yl)aniline (23)
using the general procedure from scheme 2 for the preparation of 7:

[0583] In a 500 mL round-bottomed flask was placed
3-[2,6-bis-(4-nitro-phenyl)-pyrimidin-4-yl]-8-oxa-3-aza-bicyclo[3.2.1]oct-
ane (15) in ethanol (100 ml). A catalytic amount of Pd on charcoal (wet)
was added and the mixture was stirred under a hydrogen atmosphere for 40
h. The mixture was filtered over Celite®, rinsed with MeOH, and
concentrated. The crude product was added to a silica gel column and
eluted with ethyl acetate in hexanes (40-100%) to give 295 mg of the
title compound (0.79 mmol).

Formation of urea or carbamate (25) from
3-[2,6-Bis-(4-aminophenyl)-pyrimidin-4-yl]-8-oxa-3-aza-bicyclo[3.2.1]octa-
ne (24):

[0584] To 0.8 mmol (295 mg) of
3-[2,6-bis-(4-aminophenyl)-pyrimidin-4-yl]-8-oxa-3-aza-bicyclo[3.2.1]octa-
ne (24) was added dichloromethane (8 mL) and NEt3 (0.52 mL). This
suspension was added in drops to a solution of 237 mg (0.8 mmol)
triphosgene in dichloromethane (8 mL). After 20 min, the solution was
divided over 8 vials containing excess amine or alcohol in
dichloromethane or THF. After stirring for 16 hours at room temperature
the solvents were evaporated and the mixtures were purified by HPLC
(Gilson, TFA buffers) to give the following products:

[0592] Using a solution of p-aminobenzamide in dichloromethane, the title
compound was obtained after heating for 2 hours at 50° C. (28 mg,
41%). RT 1.87. M+H=698.3.

Scheme 12

4-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloropyrimidin-2-ol (26)

[0593] In three 2-5 mL microwave vials was each placed
3-(2,6-dichloropyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (9, 100
mg, 0.384 mmol) in THF (2 ml). A 1N solution of sodium hydroxide (2 ml,
2.000 mmol) was added to each vial. The reaction was heated under
microwave irradiation at 150° C. for 30 min. The contents of the
three microwave vials were combined, 6 mL 2N HCl was added to acidify
(pH˜3). Silica gel was added and the mixture was concentrate purify
by silica gel chromatography, using a gradient (0-15%) of MeOH in
dichloromethane to give 205 mg (0.85 mmol, 74%) of the title compound as
a white solid.

Scheme 13

4,6-Di(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrimidin-2-ol (27)

[0594] In a 2-5 mL microwave vial was placed
4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloropyrimidin-2-ol (26, 50
mg, 0.207 mmol) in MeOH (2.5 ml) to give a colorless solution.
8-Oxa-3-azabicyclo[3.2.1]octane, HCl (2, 61.9 mg, 0.414 mmol) and DIPEA
(0.217 ml, 1.241 mmol) were added. The reaction was heated under
microwave irradiation at 140° C. for 30 min. Silica gel was added
and the solvents were removed under reduced pressure. The mixture was
purified by HPLC, using NH4OH buffers (Waters semi-prep LCMS) to
give the title compound (27.4 mg, 42%) as a white solid.

[0595] In a 25 mL round-bottomed flask was placed
4,6-di(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrimidin-2-ol (27), 12 mg,
0.038 mmol) in POCl3 (3 ml) to give a yellow solution. The mixture
was stirred at 100° C. for 4 h. The mixture was cool to room
temperature, poured on ice, and extracted with dichloromethane. The
organic phase was dried over MgSO4, filtered and concentrated to
give the title compound as a white crystalline solid (12 mg, 93%).

[0596] In a 2-5 mL microwave vial was placed
4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloropyrimidin-2-ol (26, 30
mg, 0.124 mmol) in iPrNH2 (2.5 ml) to give a yellow solution. The
reaction was heated under microwave irradiation at 140° C. for 30
min followed by 30 min of heating under microwave irradiation at
160° C. The solvents were removed under reduced pressure. The
residue was dissolved in dichloromethane, and purified by silica gel
chromatography, using gradient (0-10%) of MeOH in dichloromethane. The
title compound was isolated as a yellow solid (20 mg, 61%)

[0597] In a 250 mL round-bottomed flask was placed
4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(isopropylamino)pyrimidin-2-ol
(29, 124 mg, 0.469 mmol) in POCl3 (20 ml) to give a yellow solution.
The mixture was stirred at 100° C. for 16 h. The mixture was
cooled to room temperature, concentrated, diluted with dichloromethane
and washed with saturated NaHCO3 followed by 0.2 N NaOH. The organic
phase was dried over MgSO4, filtered and concentrated to give the
title compound (91 mg, 69%). Aryl chloride 30 could be transformed into
aniline 18 as described in scheme 2 for the conversion of 5 into 6.
Aniline 18 could be transformed into urea or carbamate compounds as
described in scheme 2 (and illustrated in the experimental section for
scheme 7).

[0598] 4-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloropyrimidin-2-ol (26,
460 mg, 1.903 mmol) was dissolved in 2-propanol (30 mL). The mixture was
divided over two 20 mL microwave vials. Sodium hydride (305 mg, 7.61
mmol) was added (153 mg to each vial), resulting in a fine suspension.
The vials were stirred at room temperature until no further formation of
hydrogen gas was observed. The vials were flushed with nitrogen. The
mixture was heated under microwave irradiation for 1 hour at 170°
C. The 2 vials were combined and made acidic with 9 mL 1N HCl to
pH˜3. Silica gel was added and the solvents were evaporated. Silica
gel chromatography, using a gradient (0-20%) of MeOH in dichloromethane,
gave the title compound (215 mg, 0.81 mmol, 43%) as a yellow foam.

[0599] In a 25 mL round-bottomed flask was placed
4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-isopropoxypyrimidin-2-ol (31,
215 mg, 0.810 mmol) in POCl3 (20 ml) to give a fine off-white
suspension. The mixture was stirred at 100° C. for 16 h. The
mixture was cooled to room temperature, concentrated, diluted with
dichloromethane, and washed with saturated NaHCO3. The aqueous phase
was made basic with NaOH (5N) to pH 10 and extracted with
dichloromethane. The combined organic phases were dried over MgSO4,
filtered and concentrated to give the title compound (106 mg, 46%). Aryl
chloride 32 could be transformed into aniline 19 as described in scheme 2
for the conversion of 5 into 6. Aniline 19 could be transformed into urea
or carbamate compounds as described in scheme 2 (and illustrated in the
experimental section for scheme 8).

Scheme 16

8-(2,6-Dichloropyrimidin-4-yl)-3-oxa-8-azabicyclo[3.2.1]octane (34)

[0600] In a 250 mL round-bottomed flask was placed
2,4,6-trichloropyrimidine (8, 0.575 mL, 5 mmol) in EtOH (20 mL) to give a
colorless solution. 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (33,
748 mg, 5.00 mmol) was added and the solution was cooled to 0° C.
Triethylamine (2.091 mL, 15 mmol) was added slowly and the mixture was
allowed to slowly warm to room temperature. The mixture was stirred at
room temperature for one hour and was then concentrated under reduced
pressure. The residue was dissolved in ethyl acetate and washed with sat
NaHCO3. The organic phase was dried over MgSO4, filtered and
concentrated. The crude product was added to a silica gel column and was
eluted with ethyl acetate in hexanes (5-20%) to give the title compound
(980 mg, 75%) as a white solid.

[0601] In a 250 mL round-bottomed flask was placed
8-(2,6-dichloropyrimidin-4-yl)-3-oxa-8-azabicyclo[3.2.1]octane (34, 980
mg, 3.77 mmol) in chloroform (4 ml) to give a very light yellow solution.
Sodium iodide (941 mg, 6.28 mmol) was added to give a suspension. The
mixture was cooled to 0° C. and an aqueous solution (57% w/w) of
hydrogen iodide (4.97 ml, 37.7 mmol) was added, resulting in a yellow
precipitate. The mixture was slowly warmed to room temperature and
stirred at room temperature for 4 h. The mixture was diluted with water
and quenched with NaOH (5M) to pH˜8. Aqueous sodium thiosulfate was
added to decolorize. The mixture was extracted with dichloromethane,
dried over MgSO4 and concentrated. The crude product was added to a
silica gel column and was eluted with ethyl acetate in hexanes (10-40%).
Collected fractions were concentrated to give the title compound (516 mg)
as a white solid. LCMS analysis revealed that the product contained
˜20% starting material. The mixture was used without further
purification in the next step.

[0602] In a 250 mL round-bottomed flask was placed
8-(6-chloro-2-iodopyrimidin-4-yl)-3-oxa-8-azabicyclo[3.2.1]octane (35,
627 mg, 1.783 mmol) and
4,4,5,5-tetramethyl-2-(4-nitrophenyl)-1,3,2-dioxaborolane (444 mg, 1.783
mmol) in DME (20 ml) to give an orange solution. Na2CO3 (2M
solution in water) (3.57 ml, 7.13 mmol) was added. The mixture was
degassed by bubbling nitrogen through the solution. Pd(PPh3)4
(206 mg, 0.178 mmol) was added and the mixture was heated to reflux and
stirred overnight. The mixture was diluted with ethyl acetate and washed
with a saturated solution of NaHCO3. The solids between the organic
and aqueous phase were collected by filtration and washed with
dichloromethane. The combined organic phases were dried (MgSO4) and
concentrated. The crude product was added to a silica gel column and was
eluted with ethyl acetate in hexanes (5-20%). Collected fractions were
concentrated to give the title compound (428 mg, 69%) as a yellow solid,
containing some dichloride (34, ˜20% by UV) and a trace of
OPPh3. The mixture was used without further purification in the next
step.

[0604] In a 250 mL round-bottomed flask was placed
8,8'-(2-(4-nitrophenyl)pyrimidine-4,6-diyl)bis(3-oxa-8-azabicyclo[3.2.1]o-
ctane) (37, 246 mg, 0.581 mmol) in 2-propanol (3 mL) and dichloromethane
(3 mL) to give a yellow solution. A catalytic amount of Pd on charcoal
(wet) was added and the mixture was stirred under a hydrogen atmosphere
for 4 hours. The mixture was filtered over Celite®, rinsed with
dichloromethane and concentrated. The crude product was added to a silica
gel column and was eluted with ethyl acetate in hexanes (40-60%).
Collected fractions were concentrated to give the title compound (197 mg,
0.5 mmol, 86%) as a light yellow solid. For [M+H]+ mass error=0.2 mDa or
0.46 ppm.

[0605] The following products were prepared from
4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)pyrimidin-2-yl)aniline (38)
using the general procedure from scheme 2 for the preparation of 7:

[0610] Using a solution of
(4-aminophenyl)(4-methylpiperazin-1-yl)methanone in dichloromethane, the
title compound was obtained (62 mg, 88%). RT 1.69, M+H=639.3.

Scheme 17

2,4-Dichloro-6-phenylpyrimidine (39)

[0611] A mixture of 2,4,6-trichloropyrimidine 8 (1 g, 5.45 mmol),
phenylboronic acid (665 mg, 5.45 mmol), Pd(PPh3)4 (100 mg) and
2N aqueous Na2CO3 (4.1 mL) in 1:1 toluene:EtOH (15 mL) was
heated in a microwave at 120° C. for 20 min. The reaction mixture
was diluted with EtOAc and washed with H2O and brine. The organic
layer was dried over MgSO4 and concentrated in vacuo to give
2,4-dichloro-6-phenylpyrimidine as a solid (1.35 g), which was used
without further purification in the next step.

[0613] A mixture of
3-(2-chloro-6-phenylpyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (500
mg, 1.66 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
(545 mg, 2.49 mmol), Pd(PPh3)4 (20 mg), and 2M aqueous
Na2CO3 (1.25 mL) in 1:1 toluene:EtOH (8 mL) was heated in a
microwave at 120° C. for 20 min. The reaction was repeated with
386 mg of 3-(2-chloro-6-phenylpyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]oc-
tane. The reaction mixtures were combined, diluted with EtOAc and washed
with H2O then brine. The organic layer was dried over MgSO4 and
concentrated in vacuo to give an orange oil. Silica gel chromatography
(hexane/EtOAc) gave
4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-phenylpyrimidin-2-yl)aniline
as a white solid (450 mg).

Formation of urea or carbamate compounds from
4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-phenylpyrimidin-2-yl)aniline
(41)

[0614] Target compounds were prepared using the general method from scheme
2 for the preparation of 7. Thus,
4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-phenylpyrimidin-2-yl)aniline
(41) (450 mg) was treated with triphosgene (187 mg) in Dichloromethane in
the presence of Et3N (0.883 mL). The mixture was stirred for 30 min
and was divided over 8 vials containing an excess of a primary amine or
an alcohol to give the corresponding urea or carbamate:

Formation of urea or carbamate compounds from
4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(methylsulfonylmethyl)pyrimi-
din-2-yl)aniline (44)

[0625] Target compounds were prepared using the general method from scheme
2 for the preparation of 7. Thus,
4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(methylsulfonylmethyl)pyrimi-
din-2-yl)aniline (44, 1.30 g, 3.47 mmoles) was treated with triphosgene
(0.515 g, 1.74 mmoles) in Dichloromethane in the presence of Et3N
(1.45 mL, 10.41 mmoles). The mixture was stirred for 15 min. and was
divided over 11 vials containing an excess of a primary amine or an
alcohol to give the corresponding urea or carbamate:

[0633] tert-Butyl
4-(4-(3-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(methylsulfonylmeth-
yl)pyrimidin-2-yl)phenyl)ureido)phenyl)piperazine-1-carboxylate was
obtained according to the general procedure for formation of urea or
carbamate compounds from
4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(methylsulfonylmethyl)pyrimi-
din-2-yl)aniline (44). Removal of the Boc group in tert-butyl
4-(4-(3-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(methylsulfonylmeth-
yl)pyrimidin-2-yl)phenyl)ureido)phenyl)piperazine-1-carboxylate (85.2 mg,
0.126 mmoles) by treatment with trifluoroacetic acid in dichloromethane
gave the title compound. Yield: 70.0 mg (38% over 2 steps). RT 1.64,
M+H=578.2.

[0637] tert-Butyl
4-(3-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(methylsulfonylmethyl)-
pyrimidin-2-yl)phenyl)ureido)benzyl(methyl)carbamate was prepared as
described above. Removal of the Boc group in tert-butyl
4-(3-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(methylsulfonylmethyl)-
pyrimidin-2-yl)phenyl)ureido)benzyl(methyl)carbamate (98.3 mgs, 0.154
mmoles) by treatment with trifluoroacetic acid in dichloromethane gave
the title compound. Yield: 70.8 mg (86%). RT 1.63, M+H=537.2.

[0644] Trifluoromethanesulfonic anhydride (0.084 mL, 0.499 mmol) was added
slowly to dichloromethane (1 mL) and pyridine (1 mL) at 0° C. and
stirred for 5 min at 0° C. This mixture was added to
4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloropyrimidin-2-ol (26, 93
mg, 0.384 mmol) in 1 mL dichloromethane at 0° C. The mixture was
stirred at 0° C. for 5 minutes and was then slowly warmed to room
temperature. More Tf2O was added: trifluoromethanesulfonic anhydride
(0.25 ml, 1.5 mmol) was added slowly to dichloromethane (2 ml) and
pyridine (2 ml) at 0° C. and stirred for 5 min at 0° C.
This mixture was added slowly to the reaction mixture at 0° C. and
stirred for 5 minutes at 0° C. The mixture was allowed to warm to
room temperature, stirred for 30 min and diluted with dichloromethane.
The mixture was washed with 0.5 N aqueous HCl (3×), water, and
saturated NaHCO3, dried over MgSO4 and concentrated to give the
title compound (101 mg, 70%) as an orange oil.

[0645] In a 250 mL round-bottomed flask was placed
4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloropyrimidin-2-yltrifluorome-
thanesulfonate (54, 101 mg, 0.270 mmol) and
4,4,5,5-tetramethyl-2-(4-nitrophenyl)-1,3,2-dioxaborolane (67.3 mg, 0.270
mmol) in DME (5 mL) to give an orange solution. Na2CO3 (2M
solution in water) (0.540 mL, 1.081 mmol) was added. The mixture was
degassed by bubbling nitrogen through the solution. Pd(PPh3)4
(31.2 mg, 0.027 mmol) was added. The reaction was heated to reflux and
stirred for 3 h. The mixture was diluted with ethyl acetate and washed
with a saturated solution of NaHCO3. The organic phase was dried
(MgSO4) and concentrated. The crude product was added to a silica
gel column and was eluted with ethyl acetate in hexanes (5-30%).
Collected fractions were concentrated to give the title compound (42 mg,
45%). The thus obtained compound was identical to the same compound
prepared according to Scheme 5.

Scheme 22

4-Nitrobenzimidamide, HCl (57)

[0646] In a 50 mL round-bottomed flask was placed 4-nitrobenzonitrile (55,
1 g, 6.75 mmol) in MeOH (6.75 ml) to give a yellow suspension. Sodium
methanolate (0.077 ml, 0.338 mmol) (25% by wt solution in MeOH) was added
to give an orange suspension and the mixture was stirred at room
temperature overnight at which point all solids had gone into solution.
Ammonium chloride (0.379 g, 7.09 mmol) was added and stirring was
continued overnight. A light yellow precipitate had formed. The solids
were collected by filtration and dried to give the title compound (435
mg, 32%) as a light yellow solid.

2-(4-Nitrophenyl)pyrimidine-4,6-diol (58)

[0647] In a 50 mL round-bottomed flask was placed 4-nitrobenzimidamide
(55, 0.435 g, 2.63 mmol) in MeOH (4 mL) to give a yellow suspension.
Sodium methanolate (25% by wt in MeOH) (1.867 mL, 8.17 mmol) was added.
The mixture was stirred at room temperature for 30 min. Diethyl malonate
(0.480 mL, 3.16 mmol) was added in drops and stirring was continued at
room temperature over 6 days, resulting in an orange suspension. The
mixture was concentrated, dissolved in hot water and filtered. The
filtrate was made acidic with AcOH to pH3. The resulting light yellow
solids were collected by filtration and dried under vacuum to give the
title compound (499 mg, 81%) as a light yellow solid. HRMS: For [M+H]+
mass error=-0.0 mDa or -0.17 ppm.

4,6-Dichloro-2-(4-nitrophenyl)pyrimidine (59)

[0648] In a 50 mL round-bottomed flask was placed
2-(4-nitrophenyl)pyrimidine-4,6-diol (58, 485 mg, 2.080 mmol) in
POCl3 (5 mL) to give a yellow suspension. The mixture was stirred at
100° C. for 13 hours. The mixture was concentrated, diluted with
dichloromethane and washed with saturated NaHCO3 and brine. The
organic phase was dried over MgSO4 and filtered. The filtrate was
concentrated, dissolved in a small volume of dichloromethane and filtered
over a silica gel plug (eluted with dichloromethane). The filtrate was
concentrated to give the title compound (203 mg, 36%) as a white solid.
HRMS: For [M+H]+ mass error=0.6 mDa or 2.31 ppm.

[0649] In a 250 mL round-bottomed flask was placed
4,6-dichloro-2-(4-nitrophenyl)pyrimidine (59, 192 mg, 0.711 mmol) in
dichloromethane (8 mL) to give a colorless solution.
3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (33, 106 mg, 0.711 mmol)
was added and the solution was cooled to 0° C. Triethylamine
(0.297 mL, 2.133 mmol) was added slowly and the mixture was allowed to
slowly warm to room temperature, and stirred for 16 hours at room
temperature. The mixture was heated under reflux for 2 hours, diluted
with dichloromethane and washed with saturated NaHCO3. The organic
phase was dried over MgSO4, filtered and concentrated. the crude
product was applied to a silica gel column and eluted with 5-40% EtOAc in
hexanes to give the title compound (212 mg, 86%). The sample was
identical to the same compound prepared according to Scheme 16. HRMS: For
[M+H]+ mass error=0.1 mDa or 0.39 ppm.

[0650] In a 2-5 mL microwave vial was placed
8-(6-chloro-2-(4-nitrophenyl)pyrimidin-4-yl)-3-oxa-8-azabicyclo[3.2.1]oct-
ane (36, 200 mg, 0.577 mmol) in iPrNH2 (5 mL) to give a yellow
suspension. The reaction was heated under microwave irradiation at
140° C. for 3×45 min. The mixture was concentrated. The
residue was dissolved in dichloromethane and washed with sat NaHCO3.
The organic phase was dried over MgSO4, filtered and concentrated to
give the title compound (208 mg, 98%) as a yellow foam. HRMS: For [M+H]+
mass error=0.1 mDa or 0.23 ppm.

[0651] In a 250 mL round-bottomed flask was placed
6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-isopropyl-2-(4-nitrophenyl)pyri-
midin-4-amine (60, 196 mg, 0.53 mmol) in 2-propanol (5 mL) and
dichloromethane (5 mL) to give a yellow solution. A catalytic amount of
Pd on charcoal (wet) was added and the mixture was stirred under a
hydrogen atmosphere for 16 hours. The mixture was filtered over
Celite®, rinsed with dichloromethane and concentrated to give the
title compound (176 mg, 0.52 mmol, 98%) as a yellow solid. HRMS: For
[M+H]+ mass error=0.5 mDa or 1.46 ppm.

[0652] The following products were prepared from
2-(4-aminophenyl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-isopropylpyri-
midin-4-amine (61) using the general procedure from scheme 2 for the
preparation of 7:

[0660] The title compound was prepared in 86% yield from
3-(2-chloro-6-trifluoromethyl-pyrimidin-4-yl)-8-oxa-3-aza-bicyclo[3.2.1]o-
ctane (63) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline,
using the general procedure from scheme 2 for the preparation of 6. MS
(ES.sup.+): 351.2 (M+H).sup.+.

[0661] The following products were prepared from
4-[4-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-6-trifluoromethyl-pyrimidin-2-y-
l]-phenylamine (64) using the general procedure from scheme 2 for the
preparation of 7:

[0666] Using a solution of 4-(4-methylpiperazin-1-yl)aniline in
dichloromethane, the title compound was obtained (45.4 mg, 60%). MS
(ES.sup.+): 568.3 (M+H).sup.+. RT.: 2.04 min.

[0667] The following products were prepared from
4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)pyrimidin-2-yl)aniline (38,
Scheme 16) using the general procedure from scheme 2 for the preparation
of 7:

[0669] To a solution of 2,4,5,6-tetrachloro-pyrimidine (2.0 g, 9.2 mmol)
in THF (20 mL) and triethylamine (excess) was added
3-oxa-8-aza-bicyclo[3.2.1]octane (2.7 g, 18 mmol) at -78° C. The
reaction slowly warmed to room temperature and a white precipitate
formed. To the reaction was added water (2.0 mL) and the mixture was
refluxed for three days. The reaction was cooled and water was added to
precipitate a white solid. The solids were collected by filtration and
washed with diethyl ether to yield the title compound (2.0 g). MS m/z=372
(M+H).

[0670] To a solution of
8,8'-(2,5-dichloropyrimidine-4,6-diyl)bis(3-oxa-8-azabicyclo[3.2.1]octane-
) (1.0 g, 2.7 mmol) in 1:1 ethanol:toluene (10 mL) was added
4-aminophenylboronic acid pinacol ester (0.7 g, 3.2 mmol), 2.0M solution
of sodium carbonate (1.2 mL) and tetrakis(triphenylphosphine) palladium
(0) (0.3 g, 10 mol %). The reaction was refluxed under nitrogen
overnight. The reaction was cooled and water was added (75 mL) and the
mixture was extracted 3 times with ethyl acetate. The organics were
separated and dried over magnesium sulfate, then filtered through
Magnesol® and concentrated in vacuo to an oil. The crude product was
purified via silica gel column with hexanes/ethyl acetate to yield the
title compound as a white solid (0.708 g). MS m/z=428 (M+H).

[0671] The following products were prepared from
4-(5-chloro-4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-ylpyrimidin-2-yl)anilin-
e, using the general procedure from scheme 2 for the preparation of 7:

[0675] In a 2-5 mL microwave vial was placed
9-(6-chloro-2-(4-nitrophenyl)pyrimidin-4-yl)-3,7-dioxa-9-azabicyclo[3.3.1-
]nonane (130 mg, 0.358 mmol) in isopropylamine (5 mL) to give a yellow
suspension. The reaction was heated under microwave irradiation at
145° C. for 60 min. The mixture was concentrated. The residue was
dissolved in dichloromethane and washed with saturated NaHCO3. The
organic phase was dried (MgSO4), filtered and concentrated to give
137 mg (99%) of a yellow foam. HRMS: 386.1824 [M+H].sup.+. For
[M+H].sup.+ mass error=0.1 mDa or 0.21 ppm.

[0676] In a 250 mL round bottom flask was placed
6-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-N-isopropyl-2-(4-nitrophenyl)-
pyrimidin-4-amine (124 mg, 0.32 mmol) in 2-propanol (3 mL) and
dichloromethane (3 mL) to give a yellow solution. A catalytic amount of
palladium on charcoal (wet) was added and the mixture was stirred under a
hydrogen atmosphere for 6 hours. The mixture was filtered over
Celite®, rinsed with dichloromethane and concentrated to give 110 mg
of a yellow solid (96%). HRMS: 356.2082 [M+H].sup.+. For [M+H].sup.+ mass
error=0.1 mDa or 0.29 ppm.

[0677] The following products were prepared from
2-(4-aminophenyl)-6-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-N-isopropyl-
pyrimidin-4-amine, using the general procedure from scheme 2 for the
preparation of 7:

[0681] Using a solution of 4-[2-(dimethylamino)ethoxy]aniline.2HCl in 1N
NaOH, the title compound was obtained. Yield: 17.3 mg, 37%. RT 1.68.
M+H=562.3.

Scheme 28

6-chloro-2-(4-nitrophenyl)-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-amine
and 6-chloro-N,N-diethyl-2-(4-nitrophenyl)pyrimidin-4-amine

[0682] In a 250 mL round-bottom flask was placed
4,6-dichloro-2-(4-nitrophenyl)pyrimidine (59, 500 mg, 1.85 mmol) in
dichloromethane (25 mL) to give a white suspension.
Tetrahydro-2H-pyan-4-amine, HCl (280 mg, 2.04 mmol) was added followed by
addition of triethylamine (0.77 mL, 5.55 mmol). The mixture was stirred
at room temperature for 19 hours and was then heated under reflux for 21
hour. Excess potassium carbonate was added and heating under reflux was
continued for 6 hours. The mixture was cooled to room temperature and
stirred at room temperature for 2 weeks. LCMS showed formation of the
expected product
6-chloro-2-(4-nitrophenyl)-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-amine
along with the N,N-diethylamine product
6-chloro-N,N-diethyl-2-(4-nitrophenyl)pyrimidin-4-amine. The mixture was
diluted with dichloromethane and washed with saturated NaHCO3. The
organic phase was dried (MgSO4), filtered and concentrated. The
crude product was purified by silica gel chromatography (20-60% ethyl
acetate in hexanes) to give two products:
6-chloro-2-(4-nitrophenyl)-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-amine:
152 mg (25%) of a yellow solid. HRMS: 335.0909 [M+H].sup.+. For
[M+H].sup.+ mass error=0.4 mDa or 1.15 ppm.
6-chloro-N,N-diethyl-2-(4-nitrophenyl)pyrimidin-4-amine: 72 mg. HRMS:
307.0962 [M+H].sup.+. For [M+H].sup.+ mass error=0.5 mDa or 1.73 ppm.

[0684] In a 250 mL round bottom flask was placed
6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-2-(4-nitrophenyl)-N-(tetrahydro-2-
H-pyran-4-yl)pyrimidin-4-amine (82 mg, 0.199 mmol) in dichloromethane (7
mL) and 2-propanol (7 mL). A catalytic amount of palladium on charcoal
(wet) was added and the mixture was stirred under a hydrogen atmosphere
for 16 hours. The mixture was diluted with dichloromethane, filtered over
Celite® and concentrated to give 69 mg (0.18 mmol, 91%) of a tan
solid. HRMS: 382.2236 [M+H].sup.+. For [M+H].sup.+ mass error=-0.1 mDa or
-0.35 ppm.

Alternative procedure for the preparation of
2-(4-aminophenyl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-(tetrahydro-2-
H-pyran-4-yl)pyrimidin-4-amine:

[0685] Step 1:

[0686] In a 2-5 mL microwave vial was placed
8-(6-chloro-2-(4-nitrophenyl)pyrimidin-4-yl)-3-oxa-8-azabicyclo[3.2.1]oct-
ane (36, 143 mg, 0.412 mmol) and tetrahydro-2H-pyran-4-amine.HCl (113 mg,
0.825 mmol) in dioxane to give a yellow suspension. Triethylamine (0.23
mL, 1.65 mmol) was added and the mixture was heated under microwave
irradiation at 180° C. for 30 min, followed by heating at
220° C. for 30 min. Additional tetrahydro-2H-pyran-4-amine.HCl
(113 mg) was added along with Hunig's base (0.25 mL) and the mixture was
heated for 2.5 hours at 250° C. resulting in complete conversion
of starting material into a mixture of products. The mixture contained
among others
6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-2-(4-nitrophenyl)-N-(tetrahydro-2-
H-pyran-4-yl)pyrimidin-4-amine as well as
2-(4-aminophenyl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-(tetrahydro-2-
H-pyran-4-yl)pyrimidin-4-amine. The mixture was concentrated and used in
step 2 without further purification.

[0687] Step 2:

[0688] The mixture from step 1 was dissolved in dichloromethane (7 mL) and
2-propanol (7 mL) to give a brown solution. A catalytic amount of
palladium on charcoal (wet) was added and the mixture was stirred under a
hydrogen atmosphere for 16 hours. The mixture was diluted with
dichloromethane, filtered over Celite® and concentrated. The crude
product was purified by silica gel chromatography using a gradient of
methanol and triethylamine (0-10% methanol, 0-1% NEt3) in ethyl
acetate to give 63 mg (40%) of a yellow oil.

[0689] The following products were prepared from
2-(4-aminophenyl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-(tetrahydro-2-
H-pyran-4-yl)pyrimidin-4-amine, using the general procedure from scheme 2
for the preparation of 7:

[0695] In a 250 mL round-bottom flask was placed
4,6-dichloro-2-(4-nitrophenyl)pyrimidine (59, 500 mg, 1.85 mmol) in
dichloromethane (20 mL) to give a colorless solution.
2-(methylsulfonyl)ethanamine.HCl (325 mg, 2.04 mmol) was added followed
by addition of triethylamine (0.77 mL, 5.55 mmol). The mixture was
stirred at room temperature for 19 hours and was then refluxed for 21
hour. Excess potassium carbonate was added and heating under reflux was
continued for 6 hours. The mixture was cooled to room temperature and
stirred at room temperature for 2 weeks. The mixture was diluted with
dichloromethane and washed with saturated NaHCO3. The organic phase
was dried (MgSO4), filtered and concentrated. The crude product was
purified by column chromatography (20-100% ethyl acetate in hexanes) to
give the title compound as a yellow solid (196 mg, 30%). HRMS: 357.0417
[M+H].sup.+. For [M+H].sup.+ mass error=-0.2 mDa or -0.60 ppm.

[0697] In a 250 mL round bottom flask was placed
6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-(2-(methylsulfonyl)ethyl)-2-(4--
nitrophenyl)pyrimidin-4-amine (143 mg, 0.33 mmol) in dichloromethane (7
mL) and 2-propanol (7 mL) to give a brown solution. A catalytic amount of
palladium on charcoal (wet) was added and the mixture was stirred under a
hydrogen atmosphere for 16 hours. The mixture was diluted with
dichloromethane, filtered over Celite® and concentrated to give 113 mg
(85%) of a tan solid. HRMS: 404.1751 [M+H].sup.+. For [M+H].sup.+ mass
error=-0.0 mDa or -0.07 ppm.

[0698] The following products were prepared from
2-(4-aminophenyl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-(2-(methylsul-
fonyl)ethyl)pyrimidin-4-amine, using the general procedure from scheme 2
for the preparation of 7:

[0703] Using a solution of 4-(4-methylpiperazin-1-yl)aniline in
dichloromethane, the title compound was obtained. Yield: 24.5 mg (67%).
RT 1.68, M+H=621.3

[0704] The following products were prepared from
2-(4-aminophenyl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-isopropylpyri-
midin-4-amine (61, Scheme 22) using the general procedure from scheme 2
for the preparation of 7.

[0710] In a 100 mL round bottom flask was placed
6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N,N-diethyl-2-(4-nitrophenyl)pyri-
midin-4-amine (22 mg, 0.057 mmol) in dichloromethane (2 mL) and 2-propanol
(2 mL) to give a brown solution. A catalytic amount of palladium on
charcoal (wet) was added and the mixture was stirred under a hydrogen
atmosphere for 16 hours. The mixture was diluted with dichloromethane,
filtered over Celite® and concentrated to give 17 mg (84%) of the
title compound as a tan solid. HRMS: 354.2288 [M+H].sup.+. For
[M+H].sup.+ mass error=0.0 mDa or 0.01 ppm.

[0711] The following products were prepared from
2-(4-aminophenyl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N,N-diethylpyri-
midin-4-amine, using the general procedure from scheme 2 for the
preparation of 7:

[0715] A flask was charged with
8-(2-chloro-6-(chloromethyl)pyrimidin-4-yl)-3-oxa-8-azabicyclo[3.2.1]octa-
ne (2.30 g, 8.39 mmol) and DMF (40 ml) was added to give a yellow
solution. Potassium carbonate (2.90 g, 20.97 mmol) and dimethylamine
(2.0M in THF, 4.6 ml, 9.23 mmol) were added and the reaction was allowed
to stir at room temperature for 16 hours. The reaction mixture was
filtered through a Buchner funnel and washed with methylene chloride and
ethyl acetate. The filtrate was concentrated to provide crude product as
a brown oil, which solidified upon standing (2.61 g). The crude product
was added to a silica gel column and was eluted with 0-10% methanol in
methylene chloride to provide
1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-2-chloropyrimidin-4-yl)-N,N-di-
methylmethanamine (2.01 g, 85%) as an off-white solid. HRMS; [M+H].sup.+
Obs'd=283.1320, [M+H].sup.+ Calc'd=283.1319.

[0716] A solution of
2-(4-isocyanatophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.30 g,
5.31 mmol) in toluene (50 ml) was prepared and 3-aminopyridine (0.499 g,
5.31 mmol) was added. A suspension was observed, and tetrahydrofuran (15
ml) was added. The solution was allowed to stir at room temperature for
2.5 hours, then concentrated to provide
1-(pyridin-3-yl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl-
)urea (1.82 g, quant. yield) as a tan solid, which was used without
purification.

1-cyclopropyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ure-
a

[0717] A solution of
2-(4-isocyanatophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.122 g,
0.496 mmol) in DME (3 ml) was prepared. Cyclopropylamine (0.028 g, 0.496
mmol) was added and the solution was allowed to stir at room temperature
for 20 hours. The crude DME solution was used directly in the Suzuki
reaction.

[0718] A procedure analogous to that used for the preparation of
1-cyclopropyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ur-
ea was used, using 4-(4-methylpiperazin-1-yl)aniline as the amine
component.

[0719] A procedure analogous to that used for the preparation of
1-cyclopropyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ur-
ea was used, using 4-(2-(dimethylamino)ethoxy)aniline as the amine
component.

[0720] A procedure analogous to that used for the preparation of
1-cyclopropyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ur-
ea was used, using 4-((dimethylamino)methyl)aniline as the amine
component.

[0722] A microwave vial was charged with
1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-2-chloropyrimidin-4-yl)-N,N-di-
methylmethanamine (0.080 g, 0.283 mmol) and sodium carbonate (2M in water,
0.425 mL, 0.849 mmol). DME (1.5 mL) was then added to give a yellow
biphasic solution. The solution was sparged with nitrogen for 10 minutes,
and tetrakis(triphenylphosphine)palladium(0) (0.020 g, 0.017 mmol) and
1-(pyridin-3-yl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl-
)urea (0.106 g, 0.311 mmol) were added. The vial was sealed and heated to
120° C. for 2 hours via microwave. The vessel was then cooled to
room temperature and the reaction mixture was filtered through
Celite®. The filter cake was washed with ethyl acetate and the
filtrate was washed with saturated sodium chloride and concentrated under
reduced pressure to provide a brown oil. The crude product was added to a
HPLC column and was eluted with 5-90% acetonitrile in water (0.05% TFA
buffer) to provide the mono-TFA salt of
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((dimethylamino)methyl)py-
rimidin-2-yl)phenyl)-3-(pyridin-3-yl)urea (0.097 g, 75%) as a light yellow
solid. HRMS; [M+H].sup.+ Obs'd=460.2454, [M+H].sup.+ Calc'd=460.2455.

[0723] A microwave vial was charged with a solution of
1-cyclopropyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ur-
ea (0.496 mmol) in DME (3 ml). Sodium carbonate (2M in water, 0.530 ml,
1.061 mmol), tetrakis(triphenylphosphine)palladium(0) (0.025 g, 0.021
mmol), and
1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-2-chloropyrimidin-4-yl)-N,N-di-
methylmethanamine (0.100 g, 0.354 mmol) were added and the resulting
solution was sparged with nitrogen for 5 minutes and then heated to
100° C. for 90 minutes via microwave. The vessel was then cooled
to room temperature and the reaction mixture was filtered through
Celite®. The filter cake was washed with ethyl acetate and the
filtrate was washed with saturated sodium chloride and concentrated under
reduced pressure to provide a brown oil. The crude product was added to a
HPLC column and was eluted with 5-100% acetonitrile in water (0.05% TFA
buffer) to provide the mono-TFA salt of
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((dimethylamino)methyl)py-
rimidin-2-yl)phenyl)-3-cyclopropylurea (0.073 g, 49%) as a light yellow
solid. MS; 423.2, M+H.

[0724] A procedure analogous to that used for the preparation of
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((dimethylamino)methyl)py-
rimidin-2-yl)phenyl)-3-cyclopropylurea was used, using
1-(4-(4-methylpiperazin-1-yl)phenyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-diox-
aborolan-2-yl)phenyl)urea as the boronic ester component. Yield=0.128 g,
65%. MS; 557.5, M+H.

[0725] A procedure analogous to that used for the preparation of
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((dimethylamino)methyl)py-
rimidin-2-yl)phenyl)-3-cyclopropylurea was used, using
1-(4-(2-(dimethylamino)ethoxy)phenyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dio-
xaborolan-2-yl)phenyl)urea as the boronic ester component. Yield=0.034 g,
18%. MS; 546.5, M+H.

[0726] A procedure analogous to that used for the preparation of
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((dimethylamino)methyl)py-
rimidin-2-yl)phenyl)-3-cyclopropylurea was used, using
1-(4-((dimethylamino)methyl)phenyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxa-
borolan-2-yl)phenyl)urea as the boronic ester component. Yield=0.070 g,
39%. MS; 516.5, M+H.

[0727] A procedure analogous to that used for the preparation of
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((dimethylamino)methyl)py-
rimidin-2-yl)phenyl)-3-cyclopropylurea was used, using
1-phenyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea as
the boronic ester component. Yield=0.088 g, 55%. MS; 459.5, M+H.

[0728] A microwave vial was charged with
1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-2-chloropyrimidin-4-yl)-N,N-di-
methylmethanamine (0.400 g, 1.42 mmol) and sodium carbonate (2M in water,
2.12 mL, 4.24 mmol). DME (7 mL) was then added to give a yellow biphasic
solution. The solution was degassed with nitrogen for 10 minutes, and
tetrakis(triphenylphosphine)palladium(0) (0.098 g, 0.085 mmol) and
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.372 g, 1.697
mmol) were added. The vial was sealed and heated to 120° C. for 40
minutes under microwave irradiation. LCMS indicated that the reaction had
not gone to completion. Additional
tetrakis(triphenylphosphine)palladium(0) (0.049 g, 0.043 mmol) was added
and the reaction was heated to 120° C. for an additional 80
minutes under microwave irradiation. The vessel was then cooled to room
temperature and the reaction mixture was filtered through Celite®. The
filter cake was washed with ethyl acetate and the filtrate was then
concentrated under reduced pressure to provide a brown oil. The crude
product was added to a silica gel column and was eluted with 0-10%
methanol in methylene chloride to provide
4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((dimethylamino)methyl)pyrim-
idin-2-yl)aniline (0.365 g, 76%) as a light orange solid. HRMS;
[M+H].sup.+ Obs'd=340.2133, [M+H].sup.+ Calc'd=340.2131

[0729] A solution of
4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((dimethylamino)methyl)pyrim-
idin-2-yl)aniline (0.058 g, 0.171 mmol) in dichloromethane (2 mL) was
prepared and methylisocyanate (2M in toluene, 0.214 mL, 0.427 mmol) was
added. The solution was allowed to stir at room temperature for 140
hours, then concentrated. The crude product was added to a HPLC column
and was eluted with 5-90% acetonitrile in water (0.05% TFA buffer) to
provide the mono-TFA salt of
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((dimethylamino)methyl)py-
rimidin-2-yl)phenyl)-3-methylurea (0.061 g, 90%) as a white solid. MS:
397.4, M+H.

[0730] A procedure similar to that used for the preparation of
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((dimethylamino)methyl)py-
rimidin-2-yl)phenyl)-3-methylurea was used, substituting ethylisocyanate
for methylisocyanate, to provide the mono-TFA salt of
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((dimethylamino)methyl)py-
rimidin-2-yl)phenyl)-3-ethylurea (0.014 g, 21%) as a white solid. MS:
411.4, M+H.

[0731] In a 20 mL microwave vial was placed
8-(6-chloro-2-(4-nitrophenyl)pyrimidin-4-yl)-3-oxa-8-azabicyclo[3.2.1]oct-
ane (36, 500 mg, 1.442 mmol) in toluene (15 ml) to give a yellow
suspension. The mixture was degassed with a stream of nitrogen and
tributyl(3,6-dihydro-2H-pyran-4-yl)stannane (646 mg, 1.730 mmol) and
Pd(PPH3)4 (167 mg, 0.144 mmol) were added. The reaction mixture
was heated under microwave irradiation at 150° C. for 1 hour. The
mixture was concentrated and the crude product was added to a silica gel
column and was eluted with ethyl acetate in hexanes (25-70%). Collected
fractions were concentrated to give 373 mg of a yellow solid. HRMS:
395.1707 [M+H]+. For [M+H]+ mass error=-0.6 mDa or -1.51 ppm.

[0732] In a 250 mL round-bottomed flask was placed
8-(6-(3,6-dihydro-2H-pyran-4-yl)-2-(4-nitrophenyl)pyrimidin-4-yl)-3-oxa-8-
-azabicyclo[3.2.1]octane (74, 353 mg, 0.895 mmol) in dichloromethane (10
mL) and 2-propanol (10 mL) to give a yellow solution. Pd--C (95 mg, 0.089
mmol) was added. The reaction mixture was stirred for 72 hours under an
atmosphere of hydrogen. The reaction mixture was diluted with
dichloromethane, filtered through Celite® and washed with
dichloromethane. The mixture was concentrated under reduced pressure to
give 324 mg of a yellow solid. HRMS: 367.2130 [M+H+. For [M+H]+ mass
error=0.3 mDa or 0.7 ppm.

General procedure for formation of carbamoyl or urea compounds from
4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tetrahydro-2H-pyran-4-yl)pyri-
midin-2-yl]aniline (75):

[0733] In a 250 mL round-bottomed flask was placed
4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)py-
rimidin-2-yl)aniline (75, 305 mg, 0.832 mmol) and triethylamine (0.464 ml,
3.33 mmol) in dichloromethane (7 ml) to give a yellow solution. This
mixture was added dropwise to a solution of triphosgene (123 mg, 0.416
mmol) in dichloromethane (7 ml). The mixture was stirred for 30 min and
was then divided over seven solutions (0.119 mmol to each) of amine (0.3
mmol) in 1 mL of dichloromethane. The mixture was stirred for 3 hours,
concentrated and purified by HPLC (Gilson, TFA buffers) to give the
target compounds.

[0734] The following compounds were prepared according to the general
procedure:

[0765] The assay is run by placing 5 μL of diluted enzyme per well,
then 5 μL of diluted compound (or 9.5 μL enzyme then 0.5 μL
compound in DMSO) is added and mixed. Then, 10 μL substrate is added
to start the reaction. The samples are incubated 30-60 minutes, then the
reaction is stopped by adding 20 μL stop/detector mix. PI3K is diluted
with reaction buffer (e.g., 5 μL or 7.5 μL PI3K into 620 μL
reaction buffer), and 5 μL of diluted enzyme is used per well. A 5
μL portion of reaction buffer or of drug diluted in buffer (e.g., 4
μL/100 so final DMSO is 1% in reaction) is added to each. Pipetting up
and down mixes the samples. Alternatively, the enzyme can be diluted to
1215 μL. In this case 9.8 μL is added per well and 0.2 μL
compound is added in DMSO.

[0766] To prepare 1 mL of substrate solution, 955 μL reaction buffer,
40 μL PIP2, and 2.5 μL ATP are mixed. 10 μL of substrate is
added to each well to start the reaction. This results in 20 μM PIP2,
and 25 μM ATP per reaction. The stop/detector mix is prepared by
mixing 4 μL red detector and 1.6 μL or 2.0 μL GST-GRP with 1 mL
stop buffer, which results in 10 nM probe and 70 nM GST-GRP. 20 μL of
the stop/detector mix is added to each well to stop the reaction. The
plates are read after 30-90 minutes keeping the red probe solutions dark.
For the zero time point, stop/detector mix is added to the enzyme just
before adding substrate. For an extra control, stop/detector mix is added
to buffer (no enzyme) and substrate or to just buffer (no substrate).
Pooled PI3K preparations had a protein concentration of 0.25 mg/mL. The
recommended reaction has 0.06 μL per 20 μL (0.015 μg/20 μL)
or 0.01125 μg/15 μL or 0.75 μg/mL.

[0767] Plates are read on machines with filters for TAMRA. The units are
mP with no enzyme controls reading app 190-220 mP units. Fully active
enzyme reduces fluorescence polarization down to 70-100 mP after 30
minutes. An active compound raises the mP values halfway to control or to
120-150 mP units. Compounds of the invention had IC50s against
PI3K-alpha ranging from 7 nM to 2,858 nM.

mTOR Enzyme Assay

[0768] (See Toral-Barza, et al. Biochem Biophys. Res. Commun. 2005 Jun.
24; 332(1):304-10) The routine human TOR assays with purified enzyme were
performed in 96-well plates by DELFIA format as follows. Enzymes were
first diluted in kinase assay buffer (10 mM HEPES (pH 7.4), 50 mM NaCl,
50 mM 3-glycerophosphate, 10 mM MnCl2, 0.5 mM DTT, 0.25 μM
microcystin LR, and 100 μg/mL BSA). To each well, 12 μL of the
diluted enzyme were mixed briefly with 0.5 μL test inhibitor or the
control vehicle dimethylsulfoxide (DMSO). The kinase reaction was
initiated by adding 12.5 μL kinase assay buffer containing ATP and
His6-S6K to give a final reaction volume of 25 μL containing 800 ng/mL
FLAG-TOR, 100 μM ATP and 1.25 μM His6-S6K. The reaction plate was
incubated for 2 hours (linear at 1-6 hours) at room temperature with
gentle shaking and then terminated by adding 25 μL Stop buffer (20 mM
HEPES (pH 7.4), 20 mM EDTA, 20 mM EGTA). The DELFIA detection of the
phosphorylated (Thr-389) His6-S6K was performed at room temperature using
a monoclonal anti-P(T389)-p70S6K antibody (1A5, Cell Signaling) labeled
with Europium-N1-ITC (Eu) (10.4 Eu per antibody, PerkinElmer). The DELFIA
assay buffer and enhancement solution were purchased from PerkinElmer. 45
μL of the terminated kinase reaction mixture was transferred to a
MaxiSorp plate (Nunc) containing 55 μL PBS. The His6-S6K was allowed
to attach for 2 hours after which the wells were aspirated and washed
once with PBS. 100 μL of DELFIA assay buffer with 40 ng/mL
Eu-P(T389)-S6K antibody was added. The antibody binding was continued for
1 hour with gentle agitation. The wells were then aspirated and washed 4
times with PBS containing 0.05% Tween-20 (PBST). 100 μL of DELFIA
enhancement solution was added to each well and the plates were read in a
PerkinElmer Victor model plate reader. Data obtained were used to
calculate enzymatic activity and enzyme inhibition by potential
inhibitors. Compounds of the invention had IC50 activities ranging
from <1 nM to 580 nM.

In Vitro Cell Growth Assay

[0769] The cell lines used were human prostate lines LNCap and PC3MM2,
human breast lines MDA468 and MCF7, human renal line HTB44 (A498), human
colon line HCT116, and human ovarian line OVCAR3. Cells were plated in
96-well culture plates. One day following plating, the inhibitors were
added to cells. Three days after drug treatment, viable cell densities
were determined by metabolic conversion (by viable cells) of the dye MTS,
a well-established cell proliferation assay. The assays were performed
using an assay kit purchased from Promega Corp. (Madison, Wis.) following
the protocol supplied with the kit. The MTS assay results were read in a
96-well plate reader by measuring absorbance at 490 nm. The effect of
each treatment was calculated as percent of control growth relative to
the vehicle-treated cells grown in the same culture plate. The drug
concentration that conferred 50% inhibition of growth was determined as
IC50. Compounds of the invention had IC50 activities against
LNCAP cells ranging from 6 nM to >60 uM.

[0771] Throughout this application, various publications are referenced.
The disclosures of these publications in their entireties are hereby
incorporated by reference into this application in order to more fully
describe the state of the art as known to those skilled therein as of the
date of the invention described and claimed herein.

[0772] While particular embodiments of the present invention have been
illustrated and described, it would be obvious to those skilled in the
art that various other changes and modifications can be made without
departing from the spirit and scope of the invention. It is therefore
intended to cover in the appended claims all such changes and
modifications that are within the scope of this invention.